CA3171012A1

CA3171012A1 - Heteroaryl heterocyclic compounds and uses thereof

Info

Publication number: CA3171012A1
Application number: CA3171012A
Authority: CA
Inventors: Guangxiu Dai; Kun Xiao
Original assignee: Hutchison Medipharma Ltd
Current assignee: Hutchmed Ltd
Priority date: 2020-02-20
Filing date: 2021-02-19
Publication date: 2021-08-26
Also published as: BR112022016432A2; TW202140488A; AU2021222197A1; KR20220158712A; WO2021164735A1; US20220125785A1; IL295589A; US20230043030A1; JP2023515099A; PE20221592A1; EP4107154A1; CL2022002255A1; EP4107154A4; US11478474B2; MX2022010219A; CN115151535A

Abstract

Provided herein are heteroaryl heterocyclic compounds of formula (I), pharmaceutical compositions comprising same, methods for preparing same, and uses thereof, wherein the variables are as defined in the description.

Description

DEMANDE OU BREVET VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND
PLUS D'UN TOME.

NOTE : Pour les tomes additionels, veuillez contacter le Bureau canadien des brevets JUMBO APPLICATIONS/PATENTS
THIS SECTION OF THE APPLICATION/PATENT CONTAINS MORE THAN ONE
VOLUME

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NOTE POUR LE TOME / VOLUME NOTE:

HETEROARYL HETEROCYCLIC COMPOUNDS AND USES THEREOF
Field of the Invention The present invention relates to heteroaryl heterocyclic compounds, pharmaceutical compositions comprising same, methods for preparing same, and uses thereof.
Background of the Invention Bruton's Tyrosine kinase (BTK), a member of non-receptor tyrosine protein Tee family (including BTK, LTK, TEC, BMX, TXK and the like), is widely expressed in hematopoietic cells except for T cells, NK cells and differentiated plasma cells. BTK plays an important role in signaling mediated by B cell antigen receptor (BCR) and Fcy receptor (FcyR) in B cells and myeloid cells, respectively. It is a key regulator on the B cell development, activation, signaling and survival. BTK can control the development and differentiation of B cells by activating positive regulatory factors and differentiation factors of cell cycle, and can also control the survival and proliferation of B cells by regulating the expressions of pro-apoptotic proteins and anti-apoptotic proteins. BTK also plays an important role in the migration and adhesion of B
lymphoma cells. In addition, BTK plays a role in many other hematopoietic signaling pathways, such as Toll-like receptor (TLR) and cytokine receptor-mediated TNF-a production in macrophages, signaling mediated by IgE receptor (FceRI) in mast cells, inhibition of Fas/AP0-1 induced apoptotic signal in B-type lymphoid cells, and collagen induced platelet aggregation.
In humans, BTK gene mutation would lead to a hereditary immunodeficiency disease, X-linked agammaglobulinaemia (XLA). Point mutation of BTK gene is implicated in human XLA
patients, associated with low to =detective BTK mRNA level and BTK protein expression, as a consequence, almost completely lack of the maturation and the development of B
cells and immunoglobulins, and significant attenuation of persistent calcium signal in response to BCR
stimulation. The effect of BTK mutation is only restricted on B cell populations, no significant development defects in other immune cells found in XLA patients. Spontaneous mutations of BTK gene were also found in X-linked immunodeficiency (xid) mice, showing a similar but less severe phenotype. In xid mice or mutation induced BTK gene knock-out mice, B
cell differentiation was partially blocked at the B cell stage, with reduced number of mature B cells in blood circulation, and resistance to models of collagen-induced arthritis and staphylococcus-induced arthritis. It has been indicated by a large amount of evidences that BTK is abundantly expressed in the circulating B cells in the patients with autoimmune diseases such as rheumatoid arthritis (RA), primary Sjogren's syndrome (pSS) and systemic lupus erythematosus (SLE), as well as B-cell leukemia and lymphoma. The aberrant activation of BCR signaling has been confirmed in these autoimmune diseases and B cell related diseases. Inhibition of B cells, BCR
signaling pathway and :BTK may slow down the progression of the diseases to varying degrees.
Based on the key role of BTK in the development and functions of B cells, BTK
is considered as a potential target for the treatment of B cell malignancies and autoimmune diseases. A variety of BTK inhibitors are being developed for the clinical research of hematologic malignancies and autoimmune diseases. Small molecule BTK
inhibitors (such as ibrutinib, acalabrutinib, zanubrutinib, PRN1008, GDC-0853) have shown promising therapeutic efficacies. For example, ibrutinib, an irreversible BTK inhibitor, with a relatively high durable efficacy and low toxicity in clinical studies, has been approved by U.S. Food and Drug Administration (FDA) for the treatment of relapsed mantle cell lymphoma (MCL) in 2013, chronic lymphocytic leukemia (CLL) in 2014, WaldenstrOm's macroglobulinaemia (WM) in 2015, and relapsed/refractory marginal zone lymphoma (MZL) in 2017. In particular, the approved indications were extended to chronic graft-versus-host disease (GVHD) in 2017, demonstrating the mechanism of BTK in the treatment of chronic autoimmune diseases. In addition, the irreversible BTK inhibitor acalabrutinib was approved for the treatment of adult MCL in 2017 and for CLL in 2019; zanubrutinib was approved by FDA for the treatment of MCL in November 2019; and a phase 3 study of PRN1008 against pemphigus is ongoing. Some irreversible BTK inhibitors (tirabrutinib, spebrutinib, and evobrutinib) and reversible BTK
inhibitors (GDC-0853, ARQ-531 and LOX0-305) have been on the stage of pre-clinical and clinical development.
Therefore, BTK inhibitors represent attractive therapy for the treatment of related diseases, especially cancer, inflammatory diseases or autoimmune diseases.
Summary of the Invention Provided is a compound of formula 00:

R4 X<X2 r-1 Y2, 0 (I) or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein Xi and X2 are each independently CH or N; or, Xi is N, X2 is CRia, wherein R14 is chosen from C1-6 alkyl;
X3 and Xet are each independently C or N;
Y1 and Y2 are each independently CRio or N;
R1 and R2 are each independently chosen from hydrogen, deuterium, halogen, C1_6 alkyl, C2..6 alkynyl, C1..6 haloalkyl, C3-6 cycloalkyl and phenyl; or R1 and R2 together with the carbon atoms to which they are attached form the following structures:
yOR4.
(R6)m --024 12-e.
(1-1) (1-2) (1-3) (1-4) or (1-5) , wherein rtb is independently chosen from deuterium, halogen, hydroxyl, C1-6 alkyl, C2-6 alkynyl, C1-6 deuteroalkyl and C1-6 haloalkyl; or two R6 together with the carbon atoms to which they are attached form 3-6 membered cycloalkyl; m is 0, 1, 2, 3 or 4; p is 1, 2, 3 or 4;
Z is N or CR7; R7 is chosen from hydrogen, deuterium, C1_6 alkyl, halogen and C1_6 haloalkyl;

2 or R1 and R2 together with the carbon atoms to which they are attached form provided that R3 is halogen, or both X1 and Xi are not CH at the same time;
R3 is hydrogen, deuterium, halogen or C1-6 haloalkyl;
114 is hydrogen, halogen, -CN, C1_6 alkyl, C2_6 alkynyl, -(C1.3 alkyl)-0H, -(C1_3 alkyl)-0-(C1.3 alkyl), -0-(C1_3 alkyl), -CHO, -C(0)NH2, -C(0)NHCH3, -C(0)N(CH3)2 or 3-hydroxyl-oxetan-3-yl, wherein the C1-6 alkyl or C1-3 alkyl is each optionally substituted with one or more deuterium or halo;

ON.. N N
V
s Cy is U`3)." or 22-144 ; wherein Rii is chosen from hydrogen, C1-6 alkyl and C3-6 cycloalkyl, wherein the C1-6 alkyl is optionally substituted with one or more deuterium or halo;
U, V and W are each independently N or CR12; R12 is hydrogen, deuterium or halogen;
R5 is hydrogen, C1_6 alkyl, -C(0)-(C1_6 alkyl), -C(0)-(C3_6 cycloalkyl), -C(0)-phenyl, -C(0)NH-(Ci_6 alkyl), -C(0)NH-(C3_6 cycloalkyl), -C(0)N(C1_6 alkyl)2, phenyl, 5-membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl, wherein the C1-6 alkyl, C3..6 cycloalkyl, phenyl, 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl is each optionally substituted with one or more groups chosen from:
1) halogen;
2) oxo;

3) -CN;

4) C1_6 alkyl;

5) C2_6 alkenyl;

6) C2_6 alkynyl;

7) C1-6 alkoxy;

8) C1-6 haloalkyl;

9) -(C1.6 alkyl)-0H;

10) -(C1_6 alkyl)-0-(C1_6 alkyl);

11) C3-6 cycloalkyl;

12) 3-12 membered heterocyclyl optionally substituted with one or more groups chosen from: deuterium, halogen, hydroxyl, oxo, -CN, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkynyl, C1..6 alkoxy, -(C1.6 alkyl)-CN, -(C1.6 alkyl)-0-(C1-6 alkyl), -(C1_6 alkyl)-0H, 4-6 membered heterocyclyl and deuterated 4-6 membered heterocyclyl, wherein the C1-6 alkyl, C3-6 cycloalkyl or 4-6 membered heterocyclyl is each optionally substituted with one or more groups chosen from:
deuterium, halogen, -NH2, -OH, -NH(C1_6 alkyl), -N(C1.6 alkyl)2 and -NH(C3-6 cycloalkyl);

13) 5-6 membered monocyclic heteroaryl optionally substituted with one or more groups chosen from: halogen, -CN, -(C1_6 alkyl)-CN, -(C1_6 alkyl)-0H, C1_6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, -(C1.6 alkyl)-0-(Ci_6 alkyl), -(C1_6 alkyl)-NH2, -(C1-6 alkyl)-NH(C1_6 alkyl), -(Ci_6 alkyl)-N(Ci_6 alky1)2, -(C1_6 alkyl)-NH(C3-6 cycloalkyl) and 4-6 membered heterocyclyl;

14) phenyl optionally substituted with one or more groups chosen from:
halogen, -CN, -(C1_6 alkyl)-CN, -(C1.6 alkyl)-0H, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, -(C1-6 alkyl)-0-(C1_6 alkyl), -(C1_6 alkyl)-NH2, -(C1_6 alkyl)-NH(Ci_6 alkyl), -(C1_6 alkyl)-N-(Ci..6 alky1)2, -(C1_6 alkyl)-NH(C3_6 cycloalkyl) and 4-6 membered heterocyclyl;

15) -NRa'Ra", wherein Ra' and Ra" are each independently chosen from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, -(C1_6 alkyl)-0-(Ci_6 alkyl) and 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with one or more substituents of -(C1_6 alkyl)-0H, the C1_6 alkyl is optionally substituted with one or more -NRe'lle", and R,' and Re" are each independently chosen from hydrogen, C1_6 alkyl, -(C1_6 alkyl)-OH and 4-6 membered heterocyclyl;

16) -C(0)NRb'Rb", wherein Rb' and Rb" together with the N atoms to which they are attached form 4-6 membered heterocyclyl optionally substituted with one or more groups chosen from: deuterium, halogen, -OH, C1-6 alkyl, -(C1.6 alkyl)-N112, -(C1-6 alkyl)-NH(C1-6 alkyl), -(C1-6 alkyl)-N(C1-6 alkY1)2, -(C1-6 alkyl)-NH(C3-6 cycloalkyl), -NH2, -NH(C1_6 alkyl), -N(C1_6 alky1)2, -NH(C3_6 cycloalkyl) and -(C1_6 alkyl)-0H; and

17) -C(0)R,, wherein it, is chosen from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-alkynyl, -(C1_6 alkyl)-OH and -(C1_6 alkyl)-0-(C1-6 alkyl);
R10 is hydrogen, deuterium, halogen, CN, C1-6 alkyl or C1-6 haloalkyl;
provided that if R1 and Ri together with the carbon atoms to which they are attached form the following structures:
R6 lin )1=5,r,-,1 R
ROP
*1OTN
(I-I) (I-3) 0-4) or (") , and Cy is s>11. , then the 3-12 membered heterocyclyl, when substituted, is not piperazin-l-yl substituted with C1-6 alkyl at both 2- and 6- positions.
The above compounds and the active compounds (including general structural formula compounds and specific compounds) disclosed in the context of the present invention, including pharmaceutically acceptable salts thereof, or solvates, racemic mixtures, enantiomers, diastereomers or tautomers thereof, which are covered by the above scope, are collectively referred to herein as "compounds of the present invention".
Also provided is a pharmaceutical composition, comprising the compounds of the present invention, and optionally comprising a pharmaceutically acceptable excipient.
Also provided is a method of in vivo or in vitro inhibiting the activity of BTK, comprising contacting BTK with an effective amount of the compounds of the present invention.
Also provided is a method of treating or preventing a disease mediated by BTK
or at least in part by BTK, comprising administering to the subject in need thereof an effective amount of the compounds of the present invention.

Also provided is a method of treating or preventing cancer, an inflammatory disease or autoimmune disease, comprising administering to the subject in need thereof an effective amount of the compounds of the present invention.
Also provided is a use of the compounds of the present invention for treating or preventing a disease mediated by BTK or at least in part by BTK.
Also provided is a use of the compounds of the present invention for treating or preventing cancer, an inflammatory disease or autoimmune disease.
Also provided is a use of the compounds of the present invention in the manufacture of a medicament for treating or preventing a disease mediated by BTK or at least in part by BTK.
Also provided is a use of the compounds of the present invention in the manufacture of a medicament for treating or preventing cancer, an inflammatory disease or autoimmune disease.
Also provided are the compounds of the present invention for in vivo or in vitro inhibiting the activity of BTK.
Also provided are the compounds of the present invention for use as a medicament.
Also provided is a use of the compounds of the present invention for use as a medicament for treating or preventing a disease mediated by BTK or at least in part by BTK, especially for treating or preventing cancer, an inflammatory disease or autoimmune disease.
Also provided is a pharmaceutical combination, comprising the compounds of the present invention and at least one additional therapeutic agent, wherein the therapeutic agent is preferably chosen from: an anti-inflammatory agent, an immunomodulator or an anti-tumor active agent, wherein the anti-tumor active agent includes a chemotherapeutic agent, an immune checkpoint inhibitor or agonist, and a targeted therapeutic agent.
Also provided is a kit for treating or preventing a disease mediated by BTK or at least in part by BTK. The kit can comprise the pharmaceutical composition of the present invention and instructions for use, and the pharmaceutical composition comprises the compounds of the present invention.
Brief Description of the Drawings Figure 1: Growth curve of subcutaneous transplanted tumor TMD8.
Figure 2: The inhibiting effect of the compounds of the present invention on B
cell activation in mouse whole blood induced by anti-IgD antibodies.
Figure 3: The inhibiting effect of the compounds of the present invention on B
cell activation in mouse whole blood induced by anti-IgD antibodies.
Figure 4: Effects of the compounds of the present invention on the arthrosis paw volume in CIA (collagen induced arthritis) rats (the hind paw volume was measured by a Paw Volume Meter, the data were represented by mean standard error, and each group respectively represented a normal group, a vehicle control group (i.e., the model group in the figure), compound 19 QD groups in different doses, and a 4 mg/kg GDC-0853 group (normal group: n =
3, other groups: n = 8)).
Detailed Description of the Invention Definitions As used in the present application, the following words, phrases and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.
A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -OR' refers to the attachment of R3 to the rest of the molecule through an oxygen atom.
The term "alkyl" as used herein refers to a straight or branched saturated hydrocarbon radical containing 1-18 carbon atoms (C1_18), preferably 1-10 carbon atoms (C1.10), more preferably 1-6 carbon atoms (C1_6), and further more preferably 1-4 carbon atoms (C14) or 1-3 carbon atoms (C1_3). When the term "alkyl" is prefixed with "C", it means the number of carbon atoms. For example, "C1_6 alkyl" refers to an alkyl containing 1-6 carbon atoms. "C1_3 alkyl"
refers to an alkyl containing 1-3 carbon atoms. Examples of C1-6 alkyl include, but are not limited to, methyl, ethyl, propyl (e.g. n-propyl, i-propyl), butyl (eg. n-butyl, i-butyl, s-butyl and t-butyl), pentyl (e.g. n-pentyl, i-pentyl, neo-pentyl), and hexyl, and the like.
The term "alkenyl" as used herein refers to a straight or branched unsaturated hydrocarbon radical containing one or more, for example 1, 2, or 3 carbon-carbon double bonds (C=C) and 2-

18 carbon atoms (C2..18), preferably 2-10 carbon atoms (C2-io), more preferably 2-6 carbon atoms (C2_6), and further more preferably 2-4 carbon atoms (C24). When the term "alkenyl" is prefixed with "C", it means the number of carbon atoms. For example, "C2..6 alkenyl"
refers to an alkenyl containing 2-6 carbon atoms. "C24 alkenyl" refers to an alkenyl containing 2-4 carbon atoms.
Examples of C2-6 alkenyl include, but are not limited to, vinyl, propenyl (eg.
2-propenyl), and butenyl (eg. 2-butenyl), and the like. The point of attachment for the alkenyl can be on or not on the double bonds.
The term "alkynyl" as used herein refers to a straight or branched unsaturated hydrocarbon radical containing one or more, for example 1, 2, or 3, carbon-carbon triple bonds (C--C) and 2-18 carbon atoms (C2_18), preferably 2-10 carbon atoms (C2_10), more preferably 2-6 carbon atoms (C2_6), and further more preferably 2-4 carbon atoms (C24). When the term "alkynyl" is prefixed with "C", it means the number of carbon atoms. For example, "C2..6 alkynyl"
refers to an alkynyl containing 2-6 carbon atoms. "C24 alkynyl" refers to an alkynyl containing 2-4 carbon atoms.
.. Examples of C2_6 alkynyl include, but are not limited to, ethynyl, propynyl (eg. 2-propynyl), and butynyl (eg. 2-butynyl), and the like. The point of attachment for the alkynyl can be on or not on the triple bonds.
The term "halogen" or "halo" as used herein means fluoro, chloro, bromo, and iodo, preferably fluoro, chloro and bromo, more preferably fluoro and chloro.
The term "haloalkyl" as used herein refers to an alkyl radical, as defined herein, in which one or more, for example 1, 2, 3, 4, or 5, hydrogen atoms are replaced with halogen atom, and when more than one hydrogen atoms are replaced with halogen atoms, the halogen atoms may be the same or different from each other. In one embodiment, the term "haloalkyl"
as used herein refers to an alkyl radical, as defined herein, in which two or more, such as 2, 3, 4, or 5 hydrogen atoms are replaced with halogen atoms, wherein the halogen atoms are identical to each other. In another embodiment, the term "haloalkyl" as used herein refers to an alkyl radical, as defined herein, in which two or more hydrogen atoms, such as 2, 3, 4, or 5 hydrogen atoms are replaced with halogen atoms, wherein the halogen atoms are different from each other.
When the term "haloalkyl" is prefixed with "C", it means the number of carbon atoms. For example, "C1-6 haloalkyl" refers to a haloalkyl as defined herein containing 1-6 carbon atoms. "C14 haloalkyl"
refers to a haloalkyl as defined herein containing 1-4 carbon atoms. Examples of Ci_6 haloalkyl include, but are not limited to -CF.3, -CHF2, -CH2F, -CH2CF3, -CH(CF3)2, and the like.
The term "cycloallql" as used herein refers to saturated or partially unsaturated cyclic hydrocarbon radical having 3-12 ring carbon atoms (C3-12), such as 3-8 ring carbon atoms (C34), 5-7 ring carbon atoms (C5_7), 4-7 ring carbon atoms (C4..7) or 3-6 ring carbon atoms (C3.6), which may have one or more rings, such as 1, 2, or 3 rings, preferably 1 or 2 rings.
When the term "cycloalkyl" is prefixed with "C", it means the number of carbon atoms. For example, "C3-6 cycloalkyl" or "3-6 membered cycloalkyl" refers to a cycloalkyl containing 3-6 ring carbon atoms. The cycloalkyl may include a fused or bridged ring, or a spirocyclic ring. The rings of the cycloalkyl may be saturated or has one or more, for example, one or two double bonds (i.e.
partially unsaturated), but not fully conjugated, and not an aryl as defined herein. Examples of C3_6 cycloalkyl include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[2.2]pentyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, etc.
The term "heterocyclyl" or "heterocyclic" as used herein can be used interchangeably and each refers to saturated or partially unsaturated cyclic radicals having 3-12 ring atoms, such as 3-8 ring atoms, 4-8 ring atoms, 4-6 ring atoms or 4-5 ring atoms, and containing one or more, for example 1, 2 or 3, preferably 1 or 2 heteroatoms independently chosen from N, 0 and S in the rings, with the remaining ring atoms being carbon; it may have one or more rings, for example 1, 2 or 3, preferably 1 or 2 rings. The heterocyclyl also includes those wherein the N or S
heteroatom are optionally oxidized to various oxidation states. The point of attachment of heterocyclyl can be on the N heteroatom or carbon. For example, "4-8 membered heterocyclyl"
represents a heterocyclyl having 4-8 (4, 5, 6, 7 or 8) ring atoms comprising at least one, such as 1, .. 2 or 3, preferably 1 or 2 heteroatoms independently chosen from N, 0 and S;
"4-6 membered heterocyclyl" represents a heterocyclyl having 4-6 (4, 5 or 6) ring atoms comprising at least one, preferably 1 or 2 heteroatoms independently chosen from N, 0 and S (preferably N and 0), which is preferably a monocyclic ring; and "4-5 membered heterocyclyl"
represents a heterocyclyl having 4-5 ring atoms comprising at least one, preferably 1 or 2 heteroatoms independently chosen from N, 0 and S (preferably N and 0), which is a monocyclic ring. The heterocyclyl also includes a fused or bridged ring, or a spirocyclic ring. The rings of the heterocyclyl may be saturated or has one or more, for example, one or two double bonds (i.e.
partially unsaturated), but not fully conjugated, and not a heteroaryl as defined herein. Examples of heterocyclyl include, but are not limited to: 4-8 membered heterocyclyl, 4-6 membered heterocyclyl and 4-5 membered heterocyclyl, such as oxetanyl, azetidinyl, pyrrolidyl, tetrahydrofuranyl, dioxolanyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperidyl, piperazinyl, tetrahydropyridyl, pyrazinyl, pyrazolidinyl and oxaspiro[3.3]heptyl, preferably oxetanyl (such as oxetan-3-y1), azetidinyl, tetrahydropyranyl, morpholinyl (such as morpholino), piperazinyl (such as piperazin-1-y1), tetrahydropyridyl (such as 1,2,3,6-tetrahydropyridyl).
The term "aryl" or "aromatic ring" as used herein can be used interchangeably and each refers to carbocyclic hydrocarbon radical of 6 to 14 carbon atoms consisting of one ring or more fused rings, wherein at least one ring is an aromatic ring. Examples of aryl include, but are not limited to phenyl, naphthalenyl, 1,2,3,4-tetrahydronaphthalenyl, phenanthryl, indenyl, indanyl, azulenyl, preferably phenyl and naphthalenyl.

The term "heteroaryl" or "heteroaromatic ring" as used herein can be used interchangeably and each refers to: mono-, bi-, or tri- ring system having 5-15 ring atoms, preferably 5-12 ring atoms, more preferably 5-10 ring atoms, and most preferably 5-6 or 8-10 ring atoms, wherein at least one ring is 5- or 6-membered aromatic ring containing one or more, for example 1 to 4, heteroatoms independently chosen from N, 0, and S, wherein S and N may be optionally oxidized to various oxidation states. When the total number of S and 0 atoms in the heteroaryl group exceeds 1, said S and 0 heteroatoms are not adjacent to one another.
Preferably, the heteroaryl is 5-12 membered heteroaryl. For example, the heteroaryl includes:
a 5-6 membered monocyclic heteroaryl, i.e., a monocyclic ring aromatic hydrocarbyl having 5 or 6 ring atoms, wherein the ring atoms include one or more, such as 1, 2 or 3 heteroatoms independently chosen from N, 0 and S (preferably N), and the remaining ring atoms are carbon atoms; and the heteroaryl is preferably triazolyl, pyridyl, pyrazinyl, pyrimidyl, pyrazolyl, imidazolyl, isoxazolyl, triazinyl, oxazolyl, thiadiazolyl, and pyridazinyl, more preferably triazolyl (such as 1H-1,2,3-triazole), pyridyl (such as pyridin-2-y1), pyrazinyl, and pyrimidyl, and a 8-10 membered bicyclic heteroaryl, i.e., a bicycle aromatic hydrocarbyl having 8, 9 or 10 ring atoms, wherein the ring atoms include one or more, such as 1, 2, 3 or 4, preferably 1, 2 or 3 heteroatoms independently chosen from N, 0 and S (preferably N), and the remaining ring atoms are carbon atoms, wherein at least one ring is an aromatic ring; which is preferably 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine, such as 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl.
Examples of heteroaryl include, but are not limited to: 5-6 membered monocyclic heteroaryl, such as pyridyl, N-oxide pyridyl, pyrazinyl, pyrimidyl, triazinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl (such as 1,2,4-oxadiazolyl, 1,2,5-oxadiazoly1 and 1,3,4-oxadiazoly1), thiazolyl, isothiazolyl, thiadiazolyl, tetrazolyl, triazolyl, thienyl, furanyl, pyranyl, pyrrolyl, and pyridazinyl; and a 8-10 membered bicyclic heteroaryl, such as benzooxazolyl, benzisoxazolyl, benzothienyl, benzoisothienyl, benzothiazolyl, benzoisothiazolyl, imidazopyridyl (such as imidazo[1,2-a]pyridy1), imidazopyridazinyl (such as imidazo[1,2-b]pyridazinyl), pyrrolopyridyl (such as 1H-pyrrolo[2,3-b]pyridy1), pyrrolopyrimidyl (such as pyrrolo[3,4-d]pyrimidy1), pyrazolopyridyl (such as 1H-pyrazolo[3,4-b]pyridy1), pyrazolopyrimidyl (such as pyrazolo[1,5-a]
pyrimidyl), triazolopyridyl (such as [1,2,4]triazolo[4,3-a]pyridyl and [1,2,4]
triazolo[1,5-a]pyridy1), tetrazolopyridyl (such as tetrazolo[1,5-a]pyridy1), benzofuranyl, indolyl, indazolyl, purinyl, quinolyl, isoquinolinyl, and 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine.
The term "-OH" as used herein refers to hydroxyl radical.
The term "-CN" as used herein refers to cyano radical.
The term "oxo" as used herein refers to =0.
Any asymmetric atom (e.g. carbon, etc.) of a compound of formula (I) may exist in an racemic or enantiomeric rich form, for example in (R) (S) - or (RS) -configuration. In some embodiments, asymmetric atoms have at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99%, or 100% enantiomeric excess in (R) - or (S) configurations, respectively.
When a structural formula or chemical name herein contains "(RS)", it means any mixture of (R) configuration and (S) configuration of the compound.
The term "optional" or "optionally" as used herein means that the subsequently described event or circumstance may or may not occur, and the description includes instances wherein the event or circumstance occur and instances in which it does not occur. For example, "optionally substituted with one or more" includes unsubstituted and substituted with 1, 2, 3 or more substituents as described. It will be understood by those skilled in the art, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical, chemically incorrect, synthetically non-feasible and/or inherently unstable.
The term "substituted" or "substituted with...", as used herein, means that one or more (such as, 1, 2, 3 or 4) hydrogens on the designated atom or group are replaced with one or more (such as 1, 2, 3 or 4) substituents, preferably the substituents chosen from the indicated group of substituents or radicals, provided that the designated atom's normal valence is not exceeded. The said substituents may be the same or different from each other. The term "substituted with one or more groups chosen from" or "substituted with one or more" as used herein means that one or more hydrogens on the designated atom or group are independently replaced with one or more radicals from the indicated group of substituents or radicals, wherein the said radicals may be the same or different from each other. Preferably, "substituted with one or more groups chosen from" or "substituted with one or more" means that the designated atom or group is substituted with 1, 2, 3, or 4 radicals independently chosen from the indicated group of substituents or radicals, wherein the said radicals may be the same or different from each other. In some embodiments, when a substituent is oxo (i.e., =0), then 2 hydrogens on a single atom are replaced by the oxo. An optional substituent can be any radicals, provided that combinations of substituents and/or variables result in a chemically correct and stable compound. A chemically correct and stable compound is meant to imply a compound that is sufficiently robust to survive sufficient isolation from a reaction mixture to be able to identify the chemical structure of the compound. Preferably, substituents are those exemplified in the compounds of the embodiment of the present application.
Unless otherwise specified, substituents are named into the core structure.
For example, it is to be understood that when (cycloalkypalkyl is listed as a possible substituent, the point of attachment of this substituent to the core structure is in the alkyl portion.
It will be appreciated by the person of ordinary skill in the art ("POSITA") that some of the compounds of formula (I) may contain one or more chiral centers and therefore exist in two or more stereoisomeric forms. The racemates of these isomers, the individual isomers and mixtures enriched in one enantiomer, as well as diastereomers when there are two chiral centers, and mixtures partially enriched with specific diastereomers are within the scope of the present invention. It will be further appreciated by the POSITA that the present invention includes all the individual stereoisomers (e.g. enantiomers), racemic mixtures or partially resolved mixtures of the compounds of formula (I) and, where appropriate, the individual tautomeric forms thereof.
The racemates can be used as such or can be resolved into their individual isomers. The resolution can afford stereochemically pure compounds or mixtures enriched in one or more isomers. Methods for separation of isomers are well known (cf. Allinger N. L.
and Eliel E. L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) and include physical methods such as chromatography using a chiral adsorbent. Individual isomers can be prepared in chiral form from chiral precursors. Alternatively, individual isomers can be separated chemically from a mixture by: forming diastereomeric salts with a chiral acid (such as the individual enantiomers of 10-camphorsulfonic acid, camphoric acid, alpha-bromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, and the like), fractionally crystallizing the salts, and then freeing one or both of the resolved bases, optionally repeating the process, so as obtain either or both substantially free of the other; i.e., in a form having an optical purity of > 95%. Alternatively, the racemates can be covalently linked to a chiral compound (auxiliary) to produce diastereomers which can be separated by chromatography or by fractional crystallization after which time the chiral auxiliary is chemically removed to afford the pure enantiomers, as is known to the POSITA.
The term "tautomer" as used herein refers to constitutional isomers of compounds generated by rapid movement of an atom in two positions in a molecule.
Tautomers readily interconvert into each other, e.g., enol form and ketone form are tipical tautomers.
A "pharmaceutically acceptable salt" is intended to mean a salt of a free acid or base of a compound of Formula (I) that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. For example, an acid addition salt includes such as a salt derived from an inorganic acid and an organic acid. Said inorganic acid includes such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and nitric acid; said organic acid includes such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like. For examples, see, generally, S. M. Berge, et al., "Pharmaceutical Salts", J.
Phann. Sci., 1977, 66:1-

19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002.
In addition, if a compound of the present invention herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid addition salt. Conversely, if the product is a free base, an acid addition salt, particularly a pharmaceutically acceptable acid addition salt, may be produced by dissolving the free base in a suitable solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. The POSITA will recognize various synthetic methodologies that may be used without undue experimentation to prepare non-toxic pharmaceutically acceptable acid addition salts or base addition salts.
The term "deuterated compound" or "deuterates" refers to a compound in which one or more hydrogen atoms, such as 1, 2, 3, 4 or 5 hydrogen atoms, are replaced by deuterium atoms (D).
The term "solvates" means solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the solid state, thus forming a solvate. If the solvent is water, the solvate formed is a hydrate, when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water, or less than one molecule of water, with one molecule of the substances in which the water retains its molecular state as H20, such combination being able to form one or more hydrates, for example, hemihydrate, monohydrate, and dihydrate.
As used herein, the terms "group(s)" and "radical(s)" are synonymous and are intended to indicate functional groups or fragments of molecules attachable to other fragments of molecules.
The term "active ingredient" is used to indicate a chemical substance which has biological activity. In some embodiments, an "active ingredient" is a chemical substance having pharmaceutical utility.

The term "pharmaceutical combination" as used herein means a product obtained by mixing or combining two or more active ingredients, including fixed and non-fixed combinations of active ingredients, such as a kit, and a pharmaceutical composition. The term "fixed combination" means that two or more active ingredients (such as compounds of the present invention and additional therapeutic agents) are administered simultaneously to a patient in the form of a single entity or dose. The term "non-fixed combination" means that two or more active ingredients (such as compounds of the present invention and additional therapeutic agents) are administered simultaneously, in parallel or successively to a patient in separate entities, wherein the administration provides the patient with a therapeutically effective level of the compound.
The terms "treating" or "treatment" or "prevention" of a disease or disorder, in the context of achieving therapeutic benefit, refer to administering one or more pharmaceutical substances, especially a compound of formula (I) described herein to a subject that has the disease or disorder, or has a symptom of a disease or disorder, or has a predisposition toward a disease or disorder, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, or affect the disease or disorder, the symptoms of the disease or disorder, or the predisposition toward the disease or disorder. In some embodiments, the disease or disorder is cancer, such as solid tumors or hematologic malignancies, including lymphoma, leukemia and myeloma. In another embodiment, the disease or disorder is an inflammatory diseases or autoimmune disease.
The terms "treating", "contacting" and "reacting," in the context of a chemical reaction, mean adding or mixing two or more reagents under appropriate conditions to produce the indicated and/or the desired product. It should be appreciated that the reaction which produces the indicated and/or the desired product may not necessarily result directly from the combination of two reagents which were initially added, i.e., there may be one or more intermediates which are produced in the mixture which ultimately lead to the formation of the indicated and/or the desired product.
The term "effective amount" as used herein refers to an amount or dose of an BTK
inhibiting agent sufficient to generally bring about a therapeutic benefit in patients in need of treatment for a disease or disorder mediated by BTK or at least in part by BTK. Effective amounts or doses of the active ingredient of the present disclosure may be ascertained by methods such as modeling, dose escalation studies or clinical trials, and by taking into consideration factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease or disorder, the subject's previous or ongoing therapy, the subject's health status and response to drugs, and the judgment of the attending physician.
An exemplary dose is in the range of from about 0.0001 to about 200 mg of active agent per kg of subject's body weight per day, such as from about 0.001 to 100 mg/kg/day, or about 0.01 to 35 mg/kg/day, or about 0.1 to 10 mg/kg daily in single or divided dosage units (e.g., BID, TID, QID). For a 70-kg human, an illustrative range for a suitable dosage amount is from about 0.05 to about 7 g/day, or about 0.2 to about 5 g/day. Once improvement of the patient's disease or disorder has occurred, the dose may be adjusted for maintenance treatment. For example, the dosage or the frequency of administration, or both, may be reduced as a function of the symptoms, to a level at which the desired therapeutic effect is maintained. Of course, if symptoms have been alleviated to an appropriate level, treatment may cease.
Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.

The term "inhibition" or "inhibiting" indicates a decrease in the baseline activity of a biological activity or process. The term "inhibition of BTK activity" is a practical pharmaceutical activity for purposes of this disclosure and refers to a decrease in the activity of BTK as a direct or indirect response to the presence of the compound of the present invention, relative to the activity of BTK in the absence of the compound of the present invention. The decrease in activity may be due to the direct interaction of the compound of the present invention with BTK, or due to the interaction of the compound of the present invention, with one or more other factors that in turn affect the BTK activity. For example, the presence of the compound of the present invention may decrease the BTK activity by directly binding to the BTK, by causing (directly or indirectly) another factor to decrease the BTK activity, or by (directly or indirectly) decreasing the amount of BTK present in the cell or organism.
The term "subject" or "patient" as used herein means mammals and non-mammals.
Mammals means any member of the mammalia class including, but not limited to, humans; non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, and swine; domestic animals such as rabbits, dogs, and cats;
laboratory animals including rodents, such as rats, mice, and guinea pigs; and the like. Examples of non-mammals include, but are not limited to, birds, and the like. The term "subject" or "patient" does not denote a particular age or sex. In some embodiments, the subject or patient is a human.
In general, the term "about" is used herein to modify a numerical value above or below the stated value by a variance of 20%.
Technical and scientific terms used herein and not specifically defined have the meaning commonly understood by the POSITA to which the present disclosure pertains.
All numerical ranges herein shall be interpreted as disclosing each numerical value and subset of numerical values within the range, regardless of whether they are specifically otherwise disclosed. For example, when referring to any range of values, it should be regarded as referring to every value within the range of values, for example, every integer within the range of values.
For example, C1_6 as used herein represents the inclusion of 1, 2, 3, 4, 5 or 6 C. The invention relates to all values falling within the ranges, all smaller ranges and the upper or lower limits of the numerical range.
Detailed Description of Embodiments (1):
Embodiment 1. A compound of formula (I):

R4 X:1(2'X4,=-=,.
I = R2 I

y (I) or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein X1 and X, are each independently CH or N; or, X1 is N, X2 is CR14, wherein R14 is C1-6 alkyl;
X3 and X4 are each independently C or N;

Y1 and Y2 are each independently CR10 or N;
R1 and R2 are each independently chosen from hydrogen, deuterium, halogen, C1_6 alkyl, C/-6 alkynyl, C1_6 haloalkyl, C3-6 cycloalkyl and phenyl;
or Ri and R2 together with the carbon atoms to which they are attached form the following structures:
Y=---).()R6)rTI
m ___________________________ (R6)m R6 in `2,./ "=-=-..
(0-1) (1-2) (1-3) (14) or (1-5) , wherein R6 is independently chosen from deuterium, halogen, hydroxyl, C1.0 alkyl, C2-6 alkynyl, C1-6 deuteroalkyl and C1-6 haloalkyl; or two R6 together with the carbon atoms to which they are attached form 3-6 membered cycloalkyl; m is 0, 1, 2, 3 or 4; p is 1, 2, 3 or 4;
Z is N or CR7; R7 is chosen from hydrogen, deuterium, C1_6 alkyl, halogen and C1_6 haloalkyl;
`311.
or Ri and R2 together with the carbon atoms to which they are attached form (-6) , provided that R3 is halogen, or both Xi and X, are not CH at the same time;
R3 is hydrogen, deuterium, halogen or C1-6 haloalkyl;
R4 is hydrogen, halogen, -CN, C1-6 alkyl, C2-6 alkynyl, -(Ci_3 alkyl)-0H, -(C1_3 alkyl)-0-(C1..3 alkyl), -0-(C1-3 alkyl), -CHO, -C(0)NH2, -C(0)NHCH3, -C(0)N(CH3)2 or 3-hydroxyl-oxetan-3-yl, wherein the C1-6 alkyl or C1-3 alkyl is each optionally substituted with one or more deuterium or halo;
Ril F=VY
N N
V
k'Lyikci- `-jvs<
Cy is or ; wherein R11 is chosen from hydrogen, C1-6 alkyl and C3_6 cycloalkyl, wherein the C 1_6 alkyl is optionally substituted with one or more deuterium or halo;
U, V and W are each independently N or CR12; RI, is hydrogen, deuterium or halogen;
R5 is hydrogen, C1-6 alkyl, -C(0)-(C1..6 alkyl), -C(0)-(C3-6 cycloalkyl), -C(0)-phenyl, -C(0)NH-(C1_6 alkyl), -C(0)NH-(C3_6 cycloalkyl), -C(0)N(C1_6 alky1)2, phenyl, 5-membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl, wherein the C1-6 alkyl, C3-6 cycloalkyl, phenyl, 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl is each optionally substituted with one or more groups chosen from:
1) halogen;
2) oxo;
3) -CN;
4) C1_6 alkyl;
5) C2..6 alkenyl;
6) C2_6 alkynyl;
7) C1-6 alkoxy;
8) C1_6 haloalkyl;
9) -(C1-6 alkyl)-0H;
10) -(C1-6 alkyl)-0-(C1..6 alkyl);

11) C3-6 cycloalkyl;
12) 3-12 membered heterocyclyl optionally substituted with one or more groups chosen from: deuterium, halogen, hydroxyl, oxo, -CN, Ci_6 alkyl, Ci_6 haloalkyl, C3.6 cycloalkyl, C2..6 alkynyl, C1.6 alkoxy, -(C1_6 alkyl)-CN, -(C1_6 alkyl)-0-(C1-6 alkyl), -(C1_6 alkyl)-0H, 4-6 membered heterocyclyl and deuterated 4-6 membered heterocyclyl, wherein the C1..6 alkyl, C3..6 cycloalkyl or 4-6 membered heterocyclyl is each optionally substituted with one or more groups chosen from:
deuterium, halogen, -NH2, -OH, -NH(CI.6 alkyl), -N(C1..6 alky1)2 and -NH(C3-6 cycloalkyl);
13) 5-6 membered monocyclic heteroaryl optionally substituted with one or more groups chosen from: halogen, -CN, -(C1_6 alkyl)-CN, -(C1_6 alkyl)-0H, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, -(C1.6 alkyl)-0-(Ci_6 alkyl), -(C1_6 alkyl)-NH2, -(C1-6 alkyl)-NH(Ci_6 alkyl), -(C1-6 alkyl)-N(C1-6 alkY1)2, -(C1_6 alkyl)-NH(C3-6 cycloalkyl) and 4-6 membered heterocyclyl;
14) phenyl optionally substituted with one or more groups chosen from:
halogen, -CN, -(Ci_6 alkyl)-CN, -(Ci_6 alkyl)-0H, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, -(C1-6 a lkyl)-0-(C 1-6 alkyl), -(C1-6 alkyl)-NH2, -(C1_6 alkyl)-NH(C 1 -6 alkyl), -(C1-6 alkyl)-N-(C1_6 alky1)2, -(Ci_6 alkyl)-NH(C3_6 cycloalkyl) and 4-6 membered heterocyclyl;
15) -NR,'Ra", wherein R,' and IL" are each independently chosen from hydrogen, C 1-6 alkyl, C3-6 cycloalkyl, -(CI _6 alkyl)-0-(Ci_6 alkyl) and 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with one or more substituents of -(C1_6 alkyl)-0H, the C1-6 alkyl is optionally substituted with one or more -NR,'Re", and R,' and Re" are each independently chosen from hydrogen, C1..6 alkyl, -(C1..6 alkyl)-OH and 4-6 membered heterocyclyl;
16) -C(0)NRb'Rb", wherein Rb' and Rb" together with the N atoms to which they are attached form 4-6 membered heterocyclyl optionally substituted with one or more groups chosen from: deuterium, halogen, -OH, C1..6 alkyl, -(Ci_6 alkyl)-N112, -(C1_6 alkyl)-NH(Ci_6 alkyl), -(C1_6 alkyl)-N(C1_6 alky1)2, -(C1_6 alkyl)-NH(C3-6 cycloalkyl), -NH2, -NH(C1_6 alkyl), -N(C1_6 alky1)2, -NH(C3_6 cycloalkyl) and -(C1_6 alkyl)-0H; and 17) -C(0)R, wherein Re is chosen from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -(C1_6 alkyl)-OH and -(C1_6 alkyl)-0-(C1_6 alkyl);
R10 is hydrogen, deuterium, halogen, CN, C1-6 alkyl or C1-6 haloalkyl;
provided that if R1 and R2 together with the carbon atoms to which they are attached form the following structures:
4õ--,):R6)m T11 (M) (1-3) -or (1-6) , and Cy is =\--, then the 3-12 membered heterocyclyl, when substituted, is not piperazin-l-yl substituted with C1-6 alkyl at both 2- and 6- positions;

for example, X1 and X2 are each independently CH or N; or, X1 is N, X2 is CR14, wherein R14 is C1-6 alkyl;
X3 is N, and X4 is C;
both Y1 and Y, are CH;
R3 is hydrogen, deuterium or halogen;
R1 and R, together with the carbon atoms to which they are attached form the following structures:
C),(R6)m (-3) (14) or ; wherein R6 is independently chosen from halogen, hydroxyl, C1.6 alkyl and C1-6 haloalkyl; m is 0, 1 or 2; p is 1, 2 or 3;
V)0 or Ri and R2 together with the carbon atoms to which they are attached form (I-6) , provided that R3 is halogen, or both X1 and X2 are not CH at the same time;
114 is -(C1_3 alkyl)-0H;

0 N.
V
Cy is U ; wherein R11 is Ci.6 alkyl;
both U and V are CH; and R5 is chosen from AN
e R

( N¨N N-N N N R13 \O-1/ and wherein R21 is chosen from C1_6 alkyl;
R22 is independently chosen from C1_6 alkyl, -(C1..6 alkyl)-0-(C1..6 alkyl) or membered heterocyclyl;
A1, A2 and A3 are each independently CH; and R13 is a 6 membered heterocyclyl optionally substituted with one or more substituents chosen from C1_6 alkyl and 4 membered heterocyclyl;
provided that the 6 membered heterocyclyl, when substituted, is not a piperazin-1-y1 substituted with C1_6 alkyl at both 2- and -6 positions.
preferably, R1 and R2 together with the carbon atoms to which they are attached form ,r (1-6) ,provided that R3 is halogen, or both X1 and X, are not CH at the same time;

for example, or R1 and R2 together with the carbon atoms to which they are attached form the following structure:
(1-5) ; wherein R6 is independently chosen from deuterium, halogen, hydroxyl, C1-6 alkyl, C1_6 alkynyl, C1-6 deuteroalkyl and C1-6 haloalkyl; m is 0, 1 or 2;
preferably, m is 0.
Embodiment 2. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein R1 and R2 together with the carbon atoms to which they are attached form (-1) , i.e. the compound is a compound of formula (1A):
I/R6)m R4 X=r" X3.- -' R5µ. /Cy N
I

Y2, 0 (IA) Embodiment 3. The compound of embodiment 2, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein R1 and R., together with the carbon atoms to which they are attached ,FsdRom r=vy N N
form (I-1) , X3 is N, X4 is C, Y1 is CH, Cy is and the compound is a compound of formula (11):
(Rom NC R xr2.N
N

wherein X1 and X2 are each independently CH or N; or, X1 is N, X2 is CR14, wherein R14 is chosen from C1-6 alkyl;
Y2 is CH or N;
R3 is hydrogen, deuterium, halogen or C1-6 haloalkyl;

R4 is hydrogen, halogen, -CN, C1..6 alkyl, -(C1.3 alkyl)-0H, -(C1.3 deuteroalkyl)-0H, -(C1.3 alkyl)-0-(C1.3 alkyl), -0-(C1-3 alkyl), -CHO, -C(0)N H2, -C(0)NHCH3, -C(0)N(CH3)2 or 3-hydroxyl-oxetan-3-yl, wherein the C1_6 alkyl is optionally substituted with one or more halo;
W is N or CR12, and R12 is hydrogen or halogen;
R5 is hydrogen, C1..6 alkyl, -C(0)-(C1..6 alkyl), -C(0)-(C3..6 cycloalkyl), -C(0)-phenyl, -C(0)NH-(C1.6 alkyl), -C(0)NH-(C3.6 cycloalkyl), -C(0)N(C1.6 alky1)2, phenyl, 5-membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl, wherein the C 1-6 alkyl, C3-6 cycloalkyl, phenyl, 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl is each optionally substituted with one or more groups chosen from:
1) halogen;
2) oxo;
3) -CN;
4) C1..6 alkyl;
5) C2_6 alkenyl;
6) C2_6 alkynyl;
7) C1.6 alkoxy;
8) C1-6 haloalkyl;
9) -(Ci..6 alkyl)-OH;
10) -(C1_6 alkyl)-0-(C I -6 alkyl);
11) C3-6 cycloalkyl;
12) 3-12 membered heterocyclyl optionally substituted with one or more substituents chosen from halogen, hydroxyl, oxo, -CN, C1..6 alkyl, C1..6 haloalkyl, C3-6 cycloalkyl, C2_6 alkynyl, C1..6 alkoxy, -(C1.6 alkyl)-CN, -(C1.6 alkyl)-0-(C1-alkyl), -(C1.6 alkyl)-0H, 4-6 membered heterocyclyl, 4-6 membered fluoroheterocyclyl and deuterated 4-6 membered heterocyclyl, wherein the C1..6 alkyl is optionally substituted with one or more -OH;
13) 5-6 membered monocyclic heteroaryl optionally substituted with one or more substituents chosen from halogen, -CN, -(CI _6 alkyl)-CN, -(C1-6 alkyl)-0H, C

alkyl, C3-6 cycloalkyl, C1-6 alkoxy, -(C1.6 alkyl)-0-(C 1_6 alkyl), -(C1.6 alkyl)-NH2, -(C1_6 alkyl)-NH(C1..6 alkyl), -(C1..6 alkyl)-N(Ci..6 alky1)2, -(C1.6 alkyl)-NH(C3-6 cycloalkyl) and 4-6 membered heterocyclyl;
14) phenyl optionally substituted with one or more substituents chosen from halogen, -CN, -(C1.6 alkyl)-CN, -(C1.6 alkyl)-0H, C1..6 alkyl, C3-6 cycloalkyl, C1..6 alkoxy, -(C1.6 alkyl)-0(C1.6 alkyl), -(C1.6 alkyl)-NH2, -(C1.6 alkyl)-NH(C1.6 alkyl), -(C1-6 alkyl)-N(Ci..6 alky1)2, -(C1..6 alkyl)-NH(C3..6 cycloalkyl) and 4-6 membered heterocyclyl;
15) -NRa'Ra", wherein Ra' and Re" are each independently chosen from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, -(C1.6 alkyl)-0-(C1.6 alkyl) and 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with one or more substituents of -(C1.6 alkyl)-0H, the C1-6 alkyl is optionally substituted with one or more -NRe'Re", and Re' and Re" are each independently chosen from hydrogen, C1..6 alkyl, -(C1.6 alkyl)-OH and 4-6 membered heterocyclyl;

16) -C(0)NRb'Rb", wherein Rb' and Rb" together with the N atoms to which they are attached form 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with one or more substituents chosen from halogen, -OH, C1.6 alkyl, -(C1..6 alkyl)-NH,, -(C1..6 alkyl)-NH(C1_6 alkyl), -(C1-6 alkyl)-N(C1.6 alky1)2, -(C1..6 alkyl)-NH(C3..6 cycloalkyl) and -(C1.6 alkyl)-0H; and 17) -C(0)R, wherein Re is chosen from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and -(C1.6 alkyl)-0-(C1_6 alkyl);
R6 is halogen, CI.6 alkyl or hydroxyl; and m is 0, 1, 2 or 3;
preferably, W is N or 0212, and R12 is halogen; and/or preferably, R5 is 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl optionally substituted with one or more groups chosen from:
1) C1-6 alkyl; and 2) 4-6 membered heterocycloalkyl, which is optionally substituted with C1_6 alkyl and 4-6 membered heterocyclyl;
preferably, 5-6 membered monocyclic heteroaryl is 5 membered monocyclic heteroaryl, more preferably triazoly1;
preferably, 8-10 membered bicyclic heteroaryl is 8 membered bicyclic heteroaryl, more preferably 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl.
Embodiment 4. The compound of embodiment 2, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein Ri and R, together with the carbon atoms to which they are attached Vso r4R43)n, Ri µ31e.
form (I'll , X3 is N, X4 is C, Yi is CH, Cy is , and the compound is a compound of formula (III):
R11 (Rom X
/*--V R4 X.(' IN \
HNU -`===

(III) wherein X1 and X2 are each independently CH or N; or, Xi is N, X2 is CR14, wherein R14 is chosen from C1-6 alkyl;
Y2 is CH or N;
R3 is hydrogen, deuterium, halogen or C1_6 haloalkyl;

R4 is hydrogen, halogen, -CN, C1-6 alkyl, -(C1_3 alkyl)-0H, -(Ci_3 deuteroalkyl)-0H, -(C1.3 alkyl)-0-(Ci_3 alkyl), -0-(C1-3 alkyl), -CHO, -C(0)N H2, -C(0)NHCH3, -C(0)N(CH3)2 or 3-hydroxyl-oxetan-3-yl, wherein the C1_6 alkyl is optionally substituted with one or more halo;
U and V are each independently chosen from N or CH;
R5 is hydrogen, C1_6 alkyl, -C(0)-(C1_6 alkyl), -C(0)-(C3_6 cycloalkyl), -C(0)-phenyl, -C(0)NH-(C1.6 alkyl), -C(0)NH-(C3.6 cycloalkyl), -C(0)N(C1_6 alky1)2, phenyl, 5-membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl, wherein the C1-6 alkyl, C3-6 cycloalkyl, phenyl, 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl is each optionally substituted with one or more groups chosen from:
1) halogen;
2) oxo;
3) -CN;
4) C1_6 alkyl;
5) C2_6 alkenyl;
6) C2_6 alkynyl;
7) C1-6 alkoxy;
8) C1-6 haloalkyl;
9) -(C1_6 alkyl)-OH;
10) -(C1_6 alkyl)-0-(C1-6 alkyl);
11) C3-6 cycloalkyl;
12) 3-12 membered heterocyclyl optionally substituted with one or more substituents chosen from halogen, hydroxyl, oxo, -CN, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C2_6 alkynyl, C1.6 alkoxy, -(C1_6 alkyl)-CN, -(C1_6 alkyl)-0-(C1-6 alkyl), -(C1.6 alkyl)-0H, 4-6 membered heterocyclyl, 4-6 membered fluoroheterocycly1 and deuterated 4-6 membered heterocyclyl, wherein the C1_6 alkyl is optionally substituted with one or more -OH;
13) 5-6 membered monocyclic heteroaryl optionally substituted with one or more substituents chosen from halogen, -CN, -(C1_6 alkyl)-CN, -(C1_6 alkyl)-0H, C1-alkyl, C3-6 cycloalkyl, C1_6 alkoxy, -(C1_6 alkyl)-0-(C1_6 alkyl), -(C1_6 alkyl)-N112, -(C1_6 alkyl)-NH(C1_6 alkyl), -(C1_6 alkyl)-N(Ci_6 alky1)2, -(C1_6 alkyl)-NH(C3-6 cycloalkyl) and 4-6 membered heterocyclyl;
14) phenyl optionally substituted with one or more substituents chosen from halogen, -CN, -(C1_6 alkyl)-CN, -(C1_6 alkyl)-0H, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, -(C1_6 alkyl)-0(Ci_6 alkyl), -(C1_6 alkyl)-NH2, -(C1_6 alkyl)-NH(Ci_6 alkyl), -(C1_6 alkyl)-N(Ci_6 alky1)2, -(Ci_6 alkyl)-NH(C3_6 cycloalkyl) and 4-6 membered heterocyclyl;
15) -NRa'Ra", wherein Ra' and Ra" are each independently chosen from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, -(Ci_6 alkyl)-0-(Ci_6 alkyl) and 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with one or more substituents of -(Ci_6 alkyl)-0H, the C1-6 alkyl is optionally substituted with one or more -NRe'Re", and R,' and Re" are each independently chosen from hydrogen, C1_6 alkyl, -(C1_6 alkyl)-OH and 4-6 membered heterocyclyl;

16) -C(0)NRb'Rb", wherein Rb' and Rb" together with the N atoms to which they are attached form 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with one or more substituents chosen from halogen, -OH, C1-6 alkyl, alkyl)-NH2, alkyl)-NH(C1..6 alkyl), -(C1-6 alkyl)-N(C1_6 alky1)2, -(C1_6 alkyl)-NH(C3_6 cycloalkyl) and -(C1_6 alkyl)-0H;
and 17) -C(0)R, wherein Re is chosen from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and -(C1_6 alkyl)-0-(Ci_6 alkyl);
R6 is halogen, C1.6 alkyl or hydroxyl;
m is 0, 1, 2 or 3; and R11 is hydrogen, C1_6 alkyl or Ci_6 deuteroalkyl;
provided that the 3-12 membered heterocyclyl, when substituted, is not piperazin-l-yl substituted with C1-6 alkyl at both 2- and 6- positions;
preferably, U is CH, and V is N or CH; more preferably, both U and V are CH;
preferably, R11 is C1_3 alkyl, preferably methyl or ethyl, and more preferably methyl;
preferably, 5-6 membered monocyclic heteroaryl is 6 membered monocyclic heteroaryl, more preferably pyridyl, pyrazinyl and pyrimidyl;
preferably, 5-6 membered monocyclic heteroaryl is 5 membered monocyclic heteroaryl, more preferably triazolyl;
preferably, 8-10 membered bicyclic heteroaryl is 9 membered bicyclic heteroaryl, more preferably 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl; and/or preferably, 3-12 membered heterocyclyl is 4-8 membered heterocyclyl, more preferably 4-6 membered heterocyclyl; provided that the 3-12 membered heterocyclyl, when substituted, is not piperazin-l-yl substituted with C1_6 alkyl at both 2- and 6- positions;
more preferably, 3-12 membered heterocyclyl is oxetanyl, azetidinyl, tetrahydropyranyl, morpholinyl, piperazinyl or tetrahydropyridyl; provided that the 3-12 membered heterocyclyl, when substituted, is not piperazin-l-yl substituted with C1_6 alkyl at both 2-and 6- positions.
Embodiment 5.
The compound of any one of embodiments 1-4, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein both X1 and X2 are CH, or one of X1 and X2 is N, and the other is CH;
and preferably, both X1 and X2 are CH.
Embodiment 6.
The compound of any one of embodiments 1-4, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein X1 is N, X2 is CRia, wherein R14 is chosen from C1_6 alkyl.
Embodiment 7. The compound of any one of embodiments 1-6, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein Y., is CH.

Embodiment 8. The compound of any one of embodiments 1-7, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein R3 is hydrogen or halogen.
Embodiment 9. The compound of any one of embodiments 1-8, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein R4 is C1-6 alkyl, -(C1_3 alkyl)-OH, -(C1.3 deuteroalkyl)-0H, -(C1.3 alkyl)-0-(C1_3 alkyl) or -CHO, wherein the C1_6 alkyl is optionally substituted with one or more halo;
preferably, R4 is C1-6 alkyl or -(C1.3 alkyl)-0-(C1_3 alkyl), wherein the C1..6 alkyl is substituted with one or more halo;
preferably, R4 is hydroxymethyl, hydroxy deuteromethyl, hydroxyethyl, methoxymethyl or fluoromethyl;
more preferably, R4 is hydroxymethyl or hydroxy deuteromethyl;
and more preferably, R4 is hydroxymethyl.
Embodiment 10. The compound of any one of embodiments 1-9, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein R3 is hydrogen, and R4 is -(C1_3 alkyl)-0H.
Embodiment 11. The compound of any one of embodiments 1-10, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein R5 is hydrogen, -C(0)-(C1_6 alkyl), -C(0)-(C3_6 cycloalkyl), -C(0)-phenyl, -C(0)NH-(C1_6 alkyl), -C(0)NH-(C3_6 cycloalkyl) or -C(0)N(C1_6 alky1)2.
Embodiment 12. The compound of any one of embodiments 1-10, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein R5 is 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl, wherein the 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl is each optionally substituted with one or more groups chosen from:
C3-6 cycloalkyl;
3-12 membered heterocyclyl optionally substituted with one or more C1_6 alkyl, wherein the C1_6 alkyl is substituted with one or more -OH; and -NRa'Ra", wherein Ra' and Ra" are each independently chosen from hydrogen and C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with -NRe'Re", and Re' and Re" are each independently chosen from Ci.6 alkyl, -(C1.6 alkyl)-OH
and 4-6 membered heterocyclyl;
provided that if R1 and R2 together with the carbon atoms to which they are attached form the following structures:

= R11 V
= 6/11 - ,j14$
0-1) (1-3) 0-4 Il ) or (/-6) , and Cy is , then the 3-12 membered heterocyclyl, when substituted, is not piperazin-l-yl substituted with C1-6 alkyl at both 2- and 6- positions.
Embodiment 13. The compound of any one of embodiments 1-10, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein R5 is chosen from Aj'w N
7; IN N1/2, N (1k'N R ,) tN \
(R21)11-1-1- 0 1,2/
R21 R21 R21 R24 R21 R22 "22 0---) Ai N
A r, Ai I
R
and 13 wherein R21 is chosen from C1_6 alkyl, C1.6 haloalkyl and -(C1_6 alkyl)-0-(C1_6 alkyl);
n is 0, 1 or 2;
R22 and R/3 are each independently chosen from hydrogen, -CN, C1_6 alkyl, C1_6 haloalkyl, alkyl)-0-(C1_6 alkyl), 4-6 membered heterocyclyl or -C(0)12,, and It, is chosen from hydrogen, C1-6 alkyl or -(C1_6 alkyl)-0-(C1_6 alkyl);
R24 is chosen from hydrogen, C1-6 alkyl, -(C1_6 alkyl)-0-(Ci_6 alkyl), or -C(0)NRb'Rb", wherein Rb' and Rb" together with the N atoms to which they are attached form N
A2f) membered heterocyclyl; preferably, R5 is R13 ;
A1, A2 and A3 are each independently CH or N; and R13 is chosen from:
1) hydrogen;
2) C1_6 alkyl;
3) C1-6 alkoxy;
4) halogen;
5) C3-6 cycloalkyl;
6) 3-12 membered heterocyclyl optionally substituted with one or more substituents chosen from oxo, -CN, C1-6 alkyl, C1-6 alkoxy, -(C1_6 alkyl)-CN, alkyl)-(Ci_6 alkyl), 4-6 membered heterocyclyl and deuterated 4-6 membered heterocyclyl, wherein the C1_6 alkyl is optionally substituted with one or more -OH;

7) phenyl optionally substituted with one or more substituents chosen from membered heterocyclyl;
8) -NRa'Ra", wherein Ra' and Ra" are each independently chosen from hydrogen, C1_6 alkyl, -(C1_6 alkyl)-0-(Ci_6 alkyl) and 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with -(C1_6 alkyl)-0H, the C1.6 alkyl is optionally substituted with one or more -NRe'Re", and R,' and R,"
are each independently chosen from hydrogen, C1_6 alkyl, -(C1_6 alkyl)-OH and 6 membered heterocyclyl; and 9) -C(0)NRb'Rb", wherein Rb' and Rb" together with the N atoms to which they are attached form 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with one or more C1-6 alkyl;
provided that if R1 and Ri together with the carbon atoms to which they are attached form the following structures:
r \ Rii ss _4R6)1 r =-tj R6 110 Crlsµ-/ tit iZt, v=
= n. =
(I-1) (l-3) (-4) 0-6) or , and Cy is then the 3-12 membered heterocyclyl, when substituted, is not piperazin-1-y1 substituted with C1_6 alkyl at both 2- and 6- positions.
Embodiment 14. The compound of embodiment 13, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, )1/5 wherein R13 is 3-12 membered heterocyclyl, preferably provided that if R1 and R, together with the carbon atoms to which they are attached form the following structures:
t Rii =s' em , õ
/ -===-=4sv ==, , (IA) (1-3) (1-4) `L.-'s*".= "IV
or (I-8) µ4*
, and Cy is , then the 3-12 membered heterocyclyl, when substituted, is not piperazin-1-y1 substituted with C1-6 alkyl at both 2- and 6- positions.
Embodiment 15. The compound of embodiment 13, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein R13 is piperazinyl optionally substituted with one or more substituents chosen from C1..6 alkyl and 4-5 membered heterocyclyl;
provided that if R1 and Ri together with the carbon atoms to which they are attached form the following structures:

i \
:is,,r '6------) `e' V
I. .....R6,ii, ,, .,..< , .n.i., ....,....,.., ,,, ,,,,,.
--?. .,.
\--...z.. ..,11-s1 (-1) , , 0-3) (1,4) or (I-B) , and Cy is - U '''s , then the piperazinyl, when substituted, is not piperazin-1-y1 substituted with C1-6 alkyl at both 2- and 6- positions.
Embodiment 16. The compound of any one of embodiments 1-13, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein R5 is chosen from )s. ,t=-=
iii i it I -1-. ...1.. I
A2f, A3 A2..._,.,,,, A3 i i(N
II 1 ....,.... I
A'"..(4>=N 71\
A1 ''' N
R24,,r N ). R24x N ) A2f,-: A3 =-/.'`Ns.
A, N
II I iii 1 Al N-N
A2 ,.., A3 11 1 II

,,r, 1,- Ay A3 R25, r4,...
R24. 'N N
-v- -.
FIN
? 'NO( .4%,-, ..-=

, 5 .
' A2yõ,=-= A3 '..`==

11=1, and õ R30.
, wherein R24, R24% R25, R75% R27 and R27' are each independently chosen from hydrogen, oxo and C1_6 alkyl;
R26 is C1-6 alkyl, -(CI.6 alkyl)-0-(C1-6 alkyl) or tetrahydrofuranyl;
R/8 is C1-6 alkoxy; R29 is hydrogen or -(C1_6 alkyl)-0H;
R30 is C1..6 alkyl;
A1, A2 and A3 are each independently CH or N;
preferably, both A1 and A2 are CH, or one of A1 and A2 is N, and the other is CH;
and more preferably, both A1 and A2 are CH.
Embodiment 17. The compound of any one of embodiments 1-16, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a .t.
Ai N
i i I
i 'N .. ..,-",....,õ , r-%24 tautomer thereof, wherein R5 is 0 , wherein& A2 and A3 are each independently CH or N, and R24 and R24' are each independently chosen from hydrogen, oxo and C1-6 alkyl;
and preferably, when R24 is Ci_6 alkyl (such as Ci_3 alkyl, more preferably methyl), R5 I

R24õ. N
.c N R24' is preferably 0 , wherein A1, A2 and A3 are each independently CH or N, and R24' is C1_6 alkyl (such as C1_3 alkyl, more preferably methyl), and more preferably N
A2tA3 R244.(N) Embodiment 18. The compound of embodiments 16 or 17, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein R24 and R14' are each independently chosen from hydrogen and C1..6 alkyl.
Embodiment 19. The compound of any one of embodiments 13-18, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein A1, A2 and A3 are all CH, or A1 is N and both A2 and A3 are CH, or A3 is N and both A1 and A2 are CH.
Embodiment 20. The compound of any one of embodiments 1-13, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein R5 is chosen from:
N
111 A21, =AfilV4 ="^"" Cs171 rx24 N-N \N--/
R21 ,R22 and wherein R21 is C1_6 alkyl; R, is chosen from hydrogen, C1_6 alkyl and 4 membered heterocyclyl; A1 and A2 are respectively CH; and R24 and R/4' are each independently chosen from hydrogen and C1-6 alkyl.

Embodiment 21.
The compound of any one of embodiments 4-20, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a R11 i1 R11 111 0 N, 0 N 0 N
V

"z2.0 's4 = /=
tautomer thereof, wherein is )'2.-N Or , wherein R11 is C1_6 alkyl or C1-6 deuteroalkyl;
preferably, R11 is C1_3 alkyl, preferably methyl or ethyl, and more preferably methyl;
and preferably, R11 is C1-3 deuteroalkyl, preferably trideuteromethyl.
Embodiment 22.
The compound of any one of embodiments 4-21, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein both X1 and X2 are CH, or one of X1 and X2 is N, and the other is CH; Y2 is CH; R3 is hydrogen; R4 is -(Ci..3 alkyl)-OH; U is CH, V is N or CH, and R11 is C1-3 R24., alkyl; R5 is chosen from , whereinR24 and R24' are each independently chosen from hydrogen, oxo and C1_6 alkyl, both A1 and A2 are CH, or A1 is N and A2 is CH; R6 is Ci.
6 alkyl; and m is 0 or 2.
Embodiment 23.
The compound of any one of embodiments 4-22, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein both U and V are CH, and R11 is methyl.
Embodiment 24.
The compound of any one of embodiments 1-23, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein R6 is C1_3 alkyl; and m is 2.
Embodiment 25. The compound of any one of embodiments 1-24, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein R6 is C1_3 alkyl; and in is 1.
Embodiment 26.
The compound of any one of embodiments 1-24, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein R6 is C1_6 alkyl or hydroxyl; and m is 3.
Embodiment 27.
The compound of any one of embodiments 1-26, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein R6 together with the five-membered ring to which they are ,oss :3,;10<
attached forms - .
Embodiment 28. The compound of any one of embodiments 1-27, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein 3-12 membered heterocyclyl is chosen from oxetanyl, azetidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, tetrahydropyridyl, azaoxaspiro[5.3]nonyl, diazabicyclo[2.2.1]heptyl, diazaspiro[5.2]octyl, diazaoxabicyclo[4.4.0]decyl, azaoxaspiro[5.4]decyl and diazabicyclo[3.1.1]heptyl, provided that if R1 and R2 together with the carbon atoms to which they are attached form the following structures:
= , i '1 Rii õ .,..
;K,....4R6) -_,s:....----õ, -,i.,.."----->kR6,),, A -- -,..
= . 0, ,r4 .
;
µsik.) Evp ,1/4...L.) f ., ..",..,. 'hi: .....) T v .). . .....õ .., ., Ls (I.1) , , (1-4) or (/-6) , and Cy is \--. .1-I.- ' , then the 3-12 membered heterocyclyl, when substituted, is not piperazin-1-y1 substituted with C1-6 alkyl at both 2- and 6- positions;
preferably, 3-12 membered heterocyclyl is chosen from:

1-146A i s , A. ,. 't . j. ., ( : ) õ 4., IR s , t ti I t 0 4..
e ..N
1:µ') H H N
, N and A
r -1 LN-ki' provided that if R1 and R2 together with the carbon atoms to which they are attached thrm the following structures:
s'".. --'''-, V ."6), ' g! .,'N, ii = . õ . n Is = I fr., 1 j ; ,r,, ,..,... i 0.z. ,i4...
., ,,,.. N.,.._ shi:.,....õ .../- y = , .1 ) (I-3) (1-4) (I
(i , , -6) or , and Cy is \-- 1Y- s'v'' , then the 3-12 membered heterocyclyl, when substituted, is not piperazin-1-y1 substituted with C1_6 alkyl at both 2- and 6- positions.
Embodiment 29. The compound of embodiment 4, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein both X1 and X2 are CH; Y, is CH; R3 is hydrogen; R4 is -(C1_3 alkyl)-0H; both U

N
221?
C'N") and V are CH, and R11 is methyl; R5 is chosen from 0 , wherein R24 is C1_3 alkyl, and both A1 and A2 are CH; and R6 together with the five-membered ring to which they are ;CX
attached forms -Embodiment 30. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein the compound is a compound of formula (IB) I: R5,, //C ;

Y2, 1.0 0 Yl (IB) Embodiment 31. The compound of embodiment 30, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein the compound is a compound of formula (IV):

V R4 Xf..X2'N
HN U ======

R5 Y2....O.N
(IV) wherein X1 and X, are each independently CH or N; or, X1 is N, X2 is CR14, wherein R14 is chosen from Ci_6 alkyl;
Y2 is CH or N;
R3 is hydrogen, deuterium, halogen or C1-6 haloalkyl;
R4 is hydrogen, halogen, -CN, C1_6 alkyl, -(C1_3 alkyl)-0H, -(C1_3 deuteroalkyl)-0H, -(Ci_3 alkyl)-0-(C1.3 alkyl), -0-(C1..3 alkyl), -CHO, -C(0)NH2, -C(0)NHCH3, -C(0)N(CH3)2 or 3-hydroxyl-oxetan-3-yl, wherein the Ci_6 alkyl is optionally substituted with one or more halo;
U and V are each independently chosen from N or CH;
Z is N or CH;

R5 is hydrogen, C1_6 alkyl, -C(0)-(C 1_6 alkyl), -C(0)-(C3_6 cycloalkyl), -C(0)-phenyl, -C(0)NH-(C1.6 alkyl), -C(0)NH-(C3.6 cycloalkyl), -C(0)N(C1.6 alky1)2, phenyl, 5-membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl, wherein the C1_6 alkyl, C3-6 cycloalkyl, phenyl, 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl is each optionally substituted with one or more groups chosen from:
1) halogen;
2) oxo;
3) -CN;
4) C1_6 alkyl;
5) C2_6 alkenyl;
6) C2_6 alkynyl;
7) C1_6 alkoxy;
8) C1-6 haloalkyl;
9) -(C1_6 alkyl)-0H;
10) -(Ci_6 alkyl)-0-(Ci_6 alkyl);
11) C3-6 cycloalkyl;
12) 3-12 membered heterocyclyl optionally substituted with one or more substituents chosen from halogen, hydroxyl, oxo, -CN, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C2..6 alkynyl, C1-6 alkoxy, -(Ci_6 alkyl)-CN, -(Ci_6 alkyl)-0-(C1-alkyl), -(C1.6 alkyl)-0H, 4-6 membered heterocyclyl, 4-6 membered fluoroheterocycly1 and deuterated 4-6 membered heterocyclyl, wherein the C1-6 alkyl is optionally substituted with one or more -OH;
13) 5-6 membered monocyclic heteroaryl optionally substituted with one or more substituents chosen from halogen, -CN, -(C1_6 alkyl)-CN, -(C1_6 alkyl)-OH, C1-alkyl, C3-6 cycloalkyl, C1-6 alkoxy, -(C1_6 alkyl)-0-(C1_6 alkyl), -(C1_6 alkyl)-N112, -(C1_6 alkyl)-NH(C1-6 alkyl), -(C1_6 alkyl)-N(C1-6 alky1)2, -(C1_6 alkyl)-NH(C3-6 cycloalkyl) and 4-6 membered heterocyclyl;
14) phenyl optionally substituted with one or more substituents chosen from halogen, -CN, -(C1_6 alkyl)-CN, -(C1_6 alkyl)-0H, C1-6 alkyl, C3..6 cycloalkyl, C1-6 alkoxy, -(C1_6 alkyl)-0(C1-6 alkyl), -(C1_6 alkyl)-NH2, -(C1_6 alkyl)-NH(Ci_6 alkyl), -(C1_6 alkyl)-N(Ci_6 alky02, -(C1_6 alkyl)-NH(C3_6 cycloalkyl) and 4-6 membered heterocyclyl;
15) -NRa'Ra", wherein Ra' and Ra" are each independently chosen from hydrogen, C1_6 alkyl, C3_6 cycloalkyl, -(C1_6 alkyl)-0-(C1_6 alkyl) and 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with one or more substituents of -(Ci_6 alkyl)-0H, the C1-6 alkyl is optionally substituted with one or more -NR,'Re", and Re' and R," are each independently chosen from hydrogen, C1-6 alkyl, -(C1-6 alkyl)-OH and 4-6 membered heterocyclyl;
16) -C(0)NRb'Rb", wherein Rb' and Rb" together with the N atoms to which they are attached form 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with one or more substituents chosen from halogen, -OH, C1-6 alkyl, -(C1_6 alkyl)-NH2, -(C1_6 alkyl)-NH(Ci_6 alkyl), -(C1-6 alkyl)-N(Ci_6 alky02, -(C1_6 alkyl)-NH(C3_6 cycloalkyl) and -(Ci_6 alkyl)-0H;
and 17) -C(0)R, wherein Rc is chosen from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and -(C1_6 alkyl)-0-(Ci_6 alkyl);
R6 is halogen, Ci.6 alkyl or hydroxyl;
m is 0, 1, 2 or 3; and R11 is hydrogen, C1-6 alkyl or C1-6 deuteroalkyl;
preferably, both X1 and X2 are CH, or one of X1 and X2 is N, and the other is CH;
preferably, both X1 and X2 are CH;
preferably, Y2 is CH;
preferably, R3 is hydrogen or halogen;
preferably, R4 is C1_6 alkyl, -(C1_3 alkyl)-0H, -(C1_3 deuteroalkyl)-0H, -(C1_3 alkyl)-0-(C1.3 alkyl) or -CHO, wherein the C1-6 alkyl is optionally substituted with one or more halogen; more preferably R4 is -(C1_3 alkyl)-0H;
preferably, R4 is C1_6 alkyl or -(C1_3 alkyl)-0-(Ci_3 alkyl), wherein the C1_6 alkyl is substituted with one or more halo;
preferably, R4 is hydroxymethyl, hydroxy deuteromethyl, hydroxyethyl, methoxymethyl or fluoromethyl; ; more preferably, R4 is hydroxymethyl;
preferably, R3 is hydrogen, and R4 is -(C1_3 alkyl)-0H;
R11 Iii 11 ONv ON 0 N
0 N.
N
)tilf.Lc4 = )?1.)Ls4 preferably, is or , wherein R11 is C1-6 alkyl or C1-6 deuteroalkyl;
preferably, Z is CH;
preferably, U is CH, and V is N or CH; more preferably, both U and V are CH;
preferably, both U and V are CH, and R11 is methyl;
preferably, R11 is C1_3 alkyl, preferably methyl or ethyl, and more preferably methyl;
preferably, R11 is C1-3 deuteroalkyl, preferably trideuteromethyl;
preferably, R6 is halogen;
preferably, R6 is C1-3 alkyl;
preferably, in is 0 or 1;
preferably, 5-6 membered monocyclic heteroaryl is 6 membered monocyclic heteroaryl, more preferably pyridyl, pyrazinyl and pyrimidyl;
preferably, 5-6 membered monocyclic heteroaryl is 5 membered monocyclic heteroaryl, more preferably triazolyl;
preferably, 8-10 membered bicyclic heteroaryl is 9 membered bicyclic heteroaryl, more preferably 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl; and/or and preferably, 3-12 membered heterocyclyl is 4-6 membered heterocyclyl, more preferably oxetanyl, azetidinyl, tetrahydropyranyl, morpholinyl, piperazinyl or tetrahydropyridyl.
Embodiment 32. The compound of any one of embodiments 30-31, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein Y2 is CH.

Embodiment 33.
The compound of any one of embodiments 30-32, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein R5 is hydrogen, -C(0)-(C1_6 alkyl), -C(0)-(C3-6 cycloalkyl), -C(0)-phenyl, -C(0)NH-(C1_6 alkyl), -C(0)NH-(C3_6 cycloalkyl) or -C(0)N(C1_6 alky1)2.
Embodiment 34.
The compound of any one of embodiments 30-32, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein R5 is 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl, wherein the 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl is each optionally substituted with one or more groups chosen from:
C3-6 cycloalkyl;
3-12 membered heterocyclyl optionally substituted with one or more C1_6 alkyl, wherein the C1_6 alkyl is substituted with one or more -OH; and -NRe'Re", wherein Re' and Re" are each independently chosen from hydrogen and C1_6 alkyl, wherein the C1-6 alkyl is optionally substituted with -NRe'Re", and Re' and Re" are each independently chosen from Ci_6 alkyl, -(C1..6 alkyl)-OH
and 4-6 membered heterocyclyl.
Embodiment 35. The compound of any one of embodiments 30-34, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein R5 is chosen from:

,c7.;=-7 m ;5\, (R21 P(21N¨NN 0 = R21 R:24 R21 R22 0 FL
A')NNsi A2tA3 and wherein Ril is chosen from C1_6 alkyl, C1_6 haloalkyl and -(C1_6 alkyl)-0-(C1_6 alkyl);
n is 0, 1 or 2;
R22 and R/3 are each independently chosen from hydrogen, -CN, C1_6 alkyl, C1_6 haloalkyl, -(C1_6 alkyl)-0-(Ci_6 alkyl), 4-6 membered heterocyclyl or -C(0)R, and Re is chosen from hydrogen, C1_6 alkyl or -(C1_6 alkyl)-0-(C1.6 alkyl);
R24 is chosen from hydrogen, C1-6 alkyl, -(C1_6 alkyl)-0-(C1_6 alkyl), or -C(0)NRb'llb", wherein Rb' and Rb" together with the N atoms to which they are attached form membered heterocyclyl;
A1, A2 and A3 are each independently CH or N; and R13 is chosen from:

1) hydrogen;
2) Ci_6 alkyl;
3) C1_6 alkoxy;
4) halogen;
5) C3_6 cycloalkyl;
6) 4-8 membered heterocyclyl optionally substituted with one or more substituents chosen from oxo, -CN, C1_6 alkyl, C1-6 alkoxy, -(C1_6 alkyl)-CN, -(C1_6 alkyl)-0-(C1-6 alkyl), 4-6 membered heterocyclyl and deuterated 4-6 membered heterocyclyl, wherein the C1_6 alkyl is optionally substituted with one or more -OH;
7) phenyl optionally substituted with one or more substituents chosen from 4-6 membered heterocyclyl;
8) -NRa'Ra", wherein Ra' and Ra" are each independently chosen from hydrogen, alkyl, -(C1_6 alkyl)-0-(C1_6 alkyl) and 4-6 membered heterocyclyl, wherein the membered heterocyclyl is optionally substituted with one or more -(C1_6 alkyl)-0H, the C1-6 alkyl is optionally substituted with one or more -NRe'Re", and Re' and Re"
are each independently chosen from hydrogen, C1_6 alkyl, -(C1_6 alkyl)-OH and membered heterocyclyl; and 9) -C(0)NRb'Rb", wherein RI,' and Rt," together with the N atoms to which they are attached form 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with one or more C1-6 alkyl;
.."11 ALI?

preferably, R5 is , wherein At and A2 are each independently CH or N, and R13 is 4-6 membered heterocyclyl optionally substituted with one or more substituents chosen from oxo, C1_6 alkyl, C1.6 alkoxy, -(C1_6 alkyl)-0-(C1_6 alkyl) and 4-6 membered heterocyclyl;
Ai ".= N
I I
A2 r preferably, R5 is Ree Ra" , wherein A1 and A2 are each independently CH or N;Ra' and Ra" together with the N atoms to which they are attached form 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with one or more substituents chosen from oxo, C1-6 alkyl, C1-6 alkoxy and 4-6 membered heterocyclyl;

E-, tiq N
isij preferably, R5 is R22 , wherein R22 is chosen from hydrogen, -CN, C1-6 alkyl, haloalkyl, -(CI.6 alkyl)-0-(C1_6 alkyl), 4-6 membered heterocyclyl or -C(0)11e, and ft, is chosen from hydrogen, C1-6 alkyl or -(C1_6 alkyl)-0-(C1_6 alkyl);
preferably, R13 is piperazinyl optionally substituted with one or more substituents chosen from CI.6 alkyl and 4-5 membered heterocyclyl;
preferably, R5 is chosen from:
AN 7.-Ai N -.1.
,,,,,vi , A2 .....) A3 A2N.,.., A3 AN N .,..1,-it I 1 li 1 A-rik-N
Ai -N
A2 ,_,,,,' As ='''L',':=
A= N II 1 AN N'N
R24,-.., -N-, R. A2 I A2 ..., A3 P 1 is I
A2sr.., A3 R.2,--. A3 ...r my l',3 R25.õ...../.N.,..
N" R24` R. 24`".."N I N
? HNsossj, 0.)'N'''') 6 6 .....N_.^-....R25, IN. j., n27' R28 R29 9 ; 9 9 "t.

.. ."'"N.

N., and R30 =
, wherein 124, R24', 165, R25', R77 and R27' are each independently chosen from hydrogen, oxo and C1-6 alkyl;
R26 is C1..6 alkyl, -(C1_6 alkyl)-0-(C1_6 alkyl) or tetrahydrofuranyl;
Rig is C1-6 alkoxy; R29 is hydrogen or -(C1_6 a1ky1)-0H;
R30 is C1_6 alkyl; and A1, A, and A3 are each independently CH or N;
i A':7's". N
I
R24..... N ,....
L.,,,,,,, , preferably, R5 is 0 , wherein& A2 and A3 are each independently CH or N, and R14 and R24' are each independently chosen from hydrogen, oxo and C1_6 alkyl;

preferably, when R24 is C1-6 alkyl (such as C1-3 alkyl, more preferably methyl), R5 is AAA-"N
Ay A3 R24õ..r..Nõ
, N r5,24 preferably 0 , wherein Al, A2 and A3 are each independently CH or N, and R24' is C1_6 alkyl (such as C1_3 alkyl, more preferably methyl), and more preferably A. N
ti A2,,..# A3 N
0 ;
preferably, R24 and R24' are each independently chosen from hydrogen and C1_6 alkyl;
preferably, A1, A2 and A3 are all CH, or A1 is N and both A2 and A3 are CH, or A3 is N
and both A1 and Ai are CH;
and preferably, Ai, A2 and A3 are all CH.
Embodiment 36. The compound of any one of embodiments 30-35, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein both X1 and X2 are CH, or one of X1 and X2 is N, and the other is CH;
Y2 is CH;
R3 is hydrogen;
R4 is -(Ci_3 alkyl)-0H;
Z is CH;
U is CH, and V is N or CH;
"..N
py J
Ri3 R5 is or R22 , wherein Ai and A2 are each independently CH or N, and R13 is 4-6 membered heterocyclyl optionally substituted with one or more substituents chosen from oxo, C1-6 alkyl, C1-6 alkoxy, -(C1_6 alkyl)-0-(Ci_6 alkyl) and 4-6 membered heterocyclyl; R22 is chosen from hydrogen, -CN, C1..6 alkyl, C1-6 haloalkyl, -(C1.6 alkyl)-0-(C1.6 alkyl), 4-6 membered heterocyclyl or -C(0)R<, and Itc is chosen from hydrogen, C1-6 alkyl or -(C1_6 alkyl)-0-(C1.6 alkyl);
R6 is hydrogen or halogen;

M is 0, 1 or 2; and R11 is C1.3 alkyl;
MAN, i I
A2?
N,..., .. ......-...õ
'N R24, preferably, R5 is chosen from o . whereinRm and R24' are each independently chosen from hydrogen, oxo and C1_6 alkyl, both A1 and A2 are CH, or A1 is N
and A2 is CH;
and more preferably, both Ai and A2 are CH.
Embodiment 37. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, which is chosen from:
No. Structural formula No. Structural formula 1 1 2 i 0 N OH .....1,.. N
T.JMN '-'=

. N 0 ., c N 0 ====õ" 7 I ===131 I I
'0 3 1 4 1 ¨
0.,.,N e...OH .4:¨.õ N..
,),* .,. ,-,HrL --. HN N

LN 0 ekN 1 '1'1 6 e(N
N-44 N--r:i C ---5 .

*:=:!.1 -,.. .===,),,,", HN\ N 1 yc OH ...i 6 i-r ---`.
er., s-4 6 1 .-N 0 1; eN.N
N.....A
""==(:,;.!

8 1 ....
0, ,N, OH,,õ.....-.õ .
, I,. ii 4 N \ .
',, .-I. i .4 ti y LA 6 ..--,4 es, ----c ,õ
L.) 0, ON .,x)....iN N 1:
011,4.7.,N, \ 10 =-... ....i.õ?..N, ----FIN '-=
I : I
.... 0 ,N 0 ==Iii L /?"."'L
I
r N
( ) e) 1 O'' N
<j> .

0 N.,õ-- õOHr*--,-. õIN
1 (---N ip s-, N ---)'' Cr-., N 81 ---IN1/4) I ;,: I
--.
1 =". N
,,, N
( ) 13 P----N, 14 OH 0 4,pii¨

,, HN
1 HN ''' . . '--- N ', --..,õ..N 0 .4)'''N ' ,N 6 "N: It N 'ky.-=
4, N-) N
µ...-0 15 i 16 p---11 ON N, N OH HN', ,--...\
,..õ, 'IN -' r.--- N . I ..'.. N*---HN ---, -,-..- N 0 I
c .. N 0 N
tN
0 >
/N-f N
N--) / .
17 /---=N 18 r---N
NN.,.= N OH IN,, N .õ i,i OH
HN . '',. ='' HN N'X'ArN , ----Ax, ..,......N 0 .,...--,N 6 A r ,r)s-ti (N\ .....cN-4 HN--/

,Xj.,..c.(1,1 ..

20 1 /
N OH4.24S1-- OH OyN) r (-NA-I--HI:I , "=== . --1 ..14 6 Hek4.1"I''N'tr-L4 b Cy ,-- ts y tS) ) NV
L.N
H
/

21 poi Of .. N = "), 1 0 0,1N Olir.:T3p.... ... -I
HNILle4e-`71r"---\ l'i .-....).,,4 11...#4 (3 I ....N 0 y 0 '6) ,, N ,, SINN) \ Ci 6o 23 r--.{F 24 I

N, N
6 ,N
I 4 HNa H,c7.y.'' T& 0Nct.rd =,.. . ---HN , \
: I
0.-1",4 ' .N
c!...LN

L j 1 T
"== = ,-.N C
I.., '...
<A>

HN'- i 0 N ,N rõOH .r.,..1.õN \ 0 I I I N \
,-.. N --- .
-..
i ! I
4,õ..;..N 0 e ,..., N 0 NN -N
N-N...,...f.) c ,õ.=61) N
I
, 27 OH I 28 i ,. NY 0 N OH .., _,.rs1 0,1%.,iN .,..--õ,L---9-' HN , ",-I
0 11 U,--, N 0 VI el--N
N-N
/
s'l(F
N

0..,N,N ,0Hr.,..... N \ 0 N
HN".k-'-".1.-Yri N --- HN I ( ,,.. N ---k,....;..N 0 &N 0 /
S\--F
F F

rce.73- 0 N, OH
Y i Xil =-.. N ------N Lt4 6 N LN
N-N N-N

- 34 I i 0, _. NN . .. ,OH
'-,--- - r. N Ss:(-- 0 N
HN 1,...,,j, ...,,T.,_ ===(;......N \ =
---, 11 õ., Nõ..,-,----- N --HN
I II I
0 ( 0 ,-Iji N-N I
S
F F ON) N

_ 35 I -1_ 36 I
0...__N OH ,...",, r47 0 N' alr- HN N 1.1,63¨
J 1 '`, N ----,,e., N 0 I .= N 0 N
..,-isi .),... ) N
N
0õ

0 .

t .,..OH
'1 r N D D \ 0 N 0 =-, --- I Hi- ii.
,1).321---HN N , s=-, HN N' N ---,- 0 1 ,-- N I N .
I =,t N 0il .
( ) N

D*D 40 I /
0,...,.N,/

ON
39 OHNr.,11:õNSIL-_,,._ .....
HN''''''''."-INL--HN i "N. .---1`. 2....,..,,N 0 ..,,01 ..=N 0 I
`-µ
4,õ N
( ) N

,-OH N 42 I /
0)..,N OH
--v- 't \
rN-3 HN,:r --- HN}-k-N I I, µ=== Ny-12-I N 0 ek..,N c...N 0 =-õ,.., I

--\

i :J____ 0 N :S
OH ,--., 0 N
HNN, 1 i r,OHIcN131:21¨
1 r ;IL
N --, '..
..,,...-1 N 0 J. i rj N'" N --N 0 s.'N
N,..9 y N
( ) ( ) N N

45 1 46 I _ I on ro,, cr,1 5-\--- -1-- N ---I ,N 0 ---)''N ...ii I õ-N 0 --..-...? I
HN 0, HN4` 00 I
OH

HN I., ..,.0HcfS 0 N OH cy3:::(---I I
-,-- N -----.. N --HN', , \
,N 0 -,-.1j r1 I -- N 0 ==="5I I
0 N'..--) (0 0 N'''') L,.õNõ

0i6: i0 HN r.c.r.,7312:1-\ N --- N --, \..
1 ..,N 0 õ ..,N 0 I .--, ,....6) N
.--= -1, N

51 i 52 F
0 N 0Hr.c......i.rttp----, i-- OH,N
_.... ,-=-µ>, - \ !
HNI ..'. =-.. N ---=,=1 I ---ril I , N 0 I
N
'T 1 0 's) ) I N

ox:I4Hr...õN9 54 1 HN Nyl-- \ N ---1 \
N

.-N 0 I
..,..e N,9 4õtt)4) N

o 0,.N., õõOHr,:-..., N_ \ I
HNrI N --- HN OTP:l.),6,r7r.r.,635 N ---a/ I .. N 0 I -71'N
,y1 õ.e)I) N

0 N Otir------N 4t 0 N 0Hre-criic<FF
HN I
I
`-. N *--- --I ---1 -,.. HN
I
I .., N 0 F -.'til ., N 0 -ii 1 4, 4,. 71 .) ' ) N
N

0 N 0Hr.,-..,N fio 60 I

I I r N
HN
--, N --- ---. I N ---, , --..
I ---N 0 F , N 0 F
--'," ,...,71 I I
4...,N ,, õt1:1) N N

ON OH r...7,. N . F OINIciyOHNcrii.:1-..., I
HN HN
/ ..:-.N 0 F I -%.t4 0 Br ...-.1 N

\
4, s)(R,µ, .t67N) N

63 I 6 6' 0 N OH :1112,13-1-- Ck.,õN .,õ OH
rc,(NS
I
I
'=-, N --- =-- N ---HN 1 *--, HN

I s=-ky, ) 4õ$) ) N
N

65 i 66 I
Oia x_N OHnNSIL 0N OH
HN" T `,Ti -y HN''''''''4-'''''r''"'-'1 NI11:511-1-,... N NN 6 ,... 1 1- . N
,.....,ru i ==,..õõ- N 0 e) ) ,..
N ..r;') 0.z..õõN OH _,,,=., I
..3,6,r- 0y, \ N ---HNI N' \ N "---HN , -"--5-1-N ..- N
....,? tsls, N
N--) <1>

0.,.,....,.N1` =''' 1-ININ --- HN---r, N ---I
=.,.,.,-..N 0 N ,..,..,-..N

N
N
N--) N--) /

\
71 t---=N 77 1 N \ l' OH N 0.1:16.) ri\trii.SDL
X3,,,Nicr-t----cli--- \ I N *---HN , -`=-= HN
I
0 I ,-N 0 c)...'N
-'y N-N
I

..eil) N

o 0...., NI. ...,OH 621 0 N 0Hr.,-.N #
I
\ N ---HN
i .. N 0 -..,...,- N 0 ="--'4LN
e'INJ
N-N
/ 4,'.7j) N

75 oH
I
r--..N.-0 N . F 76 0 NI,N "*IrC'N'N *
I I
^-NM
I ..-N a 1 .., -.',.. til N 0 I I
T) ) 4õ.64) N N

OH _--, I
1(6-is) 0''''''''N.1 ".. r-- N \ 0.yN 0 1 Hr......-- N \
N ---I HN

%-1--.'N I
.N 0 C ) N

_-r 6Nõ_\
I 011s1,-,,NS1--HN y , HN

I ,N 0 -1-. ' ,N 0 -0,1=.1 CI )1 .....eir).4 C ) N
N

0 NNi. ,,.OH -- 0 N 0Hrc.,(NSI--HN I ==.. I ..,... N --N 0 ./N 0 N''' N
/ /N

HN .. I
0 N 011 0. f4 (.....,:r/NSIL ., OH
N ---HN 1 . '. 1,..õi, N N N-=
i , N 0 I
,,-.N 0 ,C -"--.L--. ) II
-N,...,.. N
N

HN 1 i õOH ..r.7-,N \ Ox11õ.,01r-lr.5.--,. N \
---, N ----."-I I
..,..,-,N 0 ,,,,..-N 0 1...,N
/N-N

0,....,..N,I. ,...OHr,c,N \ 0 N OHE,..:;:tp-, HAIW.k-r-/ N -- HN - 1 -"== N "---..õ1 - N 0 ' ..--N 0 =-. N ----HN 1 ===== HN , '..
ve..- ' N 0 I
0 '''-"r:- "N ,,N 0 -y F

91 i 92 I
HO OHNy,,N) , ,N N. r"
0 N OHr.,...vi:Lp, ., N ---; b HNi N, 1 \
.11 1 I ..-N 0 -='..il i N i,,, <i> .e71) 93 I 94 i ON OHõ. 0 0 N
_. 011(--=õ r,r33 -, 1 i- N \
HN

-,. N:1 ---, µ..

; ..-N 0 ===== :1 .N 0 I
I
i,, tj ) õ1;4) .icl N
6 K;>

95 i OH 96 I
N , ...õN., \ 10,.N,i .... 1 N ---FIN i ---=
0 I , N FIN .s.------r-1,- --N ----I --õ,..-..N 0 i ......N) N 4.,. N
6 e') o N
H

DtD 98 I
0 N 0,...,N...i. ..,OH
HNs..r,N \
I 1 H1e3321(----N H2NrN --......= y ....,N 0 I
4) j o 99 i 100 I
0 N 0 0 N 111-1r1,6Y¨

I I
'--.. N --- -.. N ---I I --s..,..-,N 0 N 0 -'"11 N'%.. I
hl 1 ,,,.
0 .e';') N

0.k,......N., D OH ,-.. 0 I PS) rS
HN-r HN
- I
,-. '',.. N;( ---N ----.-N 0 --'*1.-N µ=-..,N
6õ, N 6õ
) .r.)1) N N
D
c..
"'-=N

, ,--, .k......õ-T -OH
0...,..õ..-N, ,,,Ol HN1 N ....-I I
F 0 .N 0 =-õ,,..-, --N:LN N 0 ...,,T... ..j.i 6...r;j) 6,, N t f)) <j) N

v r:
0 N,. F ,,NS
-... 0 N
I TrI¨ O \
".. N --1-IN '',..

I 7 ..-N 0 -y /.., 1 N \-20 ON r,õ1,60(114.4....N \
'-... I N "--',. I 1 NNirltz.
HN 1 '''..
i L-, ri o -.- N 0 --'N
Eti y N

N---?
L.) , o ik \ N
109 I 110 i 0.x..N
HN HN i,_1 .4..)Hic., ,N \
i. N...11 N 0 ..$N
)---5:1-----,, N ---- , "--I s''. ..,-.I N 0 , N
s2) i N
\

1 1 1 I L. 112 i 1 1---- N.
I
`.. , ,=*...{Ny-1-------I ' _I I
, N 0 S .-N 0 N
\ N
N N
N
d , 0,-.....N,..

---HN

I

y i,,,. N
) N

o yi..../
0 N 0Hr, 1,1(6 E ... 0N Ile-o'N s i -,, N ---HN , ',.
N 0 (-f,/
I I ,N 6 -- jN \ , ( 1R3) ) \
O\ & i 118 1 0 N) He", 117 .... N HN N --- 1 =-.. N --- ,N 6 I -NO
......ssfsi \ , - 7..) N
N
NSI) d 0 , 1 121 i 0 N 0, N
HN ''' % ./....a...4141' N......:\

I I
.N 0 , N 0 .....1's'N
N----/ N
119 ( o ) \ o & \
120 0, .4 i,ii....N 122 1 7 ),,.,õ r;LI(LS5.1- HN 0 N N_i---I
HN --. N,Tri--S

%.::''''' N
.1.'" N -N 0 N N
N
r....---) \

123 01 64 rol,(NSI 124 1 0 N 0Hr.yrSII
,- N 0 I

rs) k 0 .c Ne N-1 --N
bo C--0 125 I 0 N ' 126 1 OH,...... ;...,,.,..1 .". r--- N
I
HN 'Wkr./ N

I
===õ,,,I N 0 N,..../ 11 N 0 ==-'... list /
I I
0.., 127 i 130 1 0 0 N 01-1.7 , HN N "===
HN (-2.1(3 ... N 0 I CiA0 NH
'NH

131 i 132 1 0Hr,:irNi3J¨ OK , 23:211¨
I
,... --- I
HN , `,..
I N HN '-.. N ---* 0 .... N 0 ..,--1.1;1 I
-,,,..,., N 0 133 1 1 i 0 N 34 0 N tsr6s:j ; I
=-, N --- ====, ---HN N
I -N 0 I .., N 0 -=,-,,, \ P
I N
0..., N--) ON 1,...,..011 HN '''',.( ., 1 \ i 1 A".......,1/4c..N ---\. N ----====, / .., N 0 \ Nti \ N N
(54) N
N--) 136 il N
&

il 0,,.N 0140;621-0 N y19, HN '-=-=
-===, HN 1 'N. N "-- s,,..-.N 6 N
' .. N 0 EN
N

cN d HN 1 N.
o N 0114 0-.N \ 0 N , --... `.. I N.,(6 HN
I . 1 N 0 I . N 0 I ..--"
Y N
<I
o ON Olsr,N \ 0;.....õ. N.,.
I
N ----N. N 'N-HN
I . E
N 0 .I.,....,N 0 ..-.11 N
N
N--) N ,, ;3 rNi:11¨
I OH (,21,9 HNX16144 \ HN
I . N 0 I . N 0 \ , N N
i ) N--) N--' ii 0....N. ,...OH rõ N \
I

HN rN HN
l'sril33----^ I
',... N ----t=N
,.-N 0 N I
N7) 0...,.

\

fl O N.. N OH r.,..; 0 N
I
N ---HN
/ . N 0 ...,..-H N 0 -=''' N

t-,1,,I
N-, N N
N--) \

I 150 i 0 N ,-hr7,N = 0 N 0 N :"'---N1 0 F
'N. I
..,.. N =,,...:1 N 0 N. 1 4, tS) ) ..6) N N

0 N 01-14,,,N # 0 N .:( N 0 6:1 =-.. --- I
HN I %.N , N ---HN., 1 '...
I ...
---.131 I
I
=-=11 0 I
N
Y
6 0.,õ
o 0 N OHE,....SD,. or...õ.1...õ,..4i HN
I
..õ 1 N HN
---- -.1 N --N.
I % ...N 0 s 1 ..,..cN 0 / N o N Nk_ /k.. N /
o \ \

0,,,õ. N ..,. OHr,N \ 0 N
.., I HN I
I
-'..' N '--I I
.= N 0 ,.-14 0 E'N
IV N
0--) 0_.) 157 I 158 0 r HNi4 1 0 N 014,,,-.. ,N \
, , 1 -N, N '-- HN =-=-. N 1 1 T . ,c --- NO I ,N 0 /.,.N
I I
) t) ) N
N

o I
o N
fõ.0Hr....;ri ,....s c .1--/
N ---i Ai 0 _. N 0 -',- y .45-Lts1 I
II
.N
N tS) ) <1? N
0õ 6 _ .. N ---HNµ , --..
F
(N ,,N 0 N
s) ) 0) N

163 I 164 i 0,-..,...,N,i ,...01-14,,,,N f\-- t p ON
N 0 3...,61-14,1(Sf-, N \
HN-* 1 µ===
-..õ--I ,N 0 %i 'N
N N
N--) N-) d , 0 N 01-6,:;621¨ 0 N
I
HN N ---I

N
N N
N--) N¨) d o 167 I i 168 0 NI
0,..N OH ..,,N 011 HNii.,=-=
--e. \
HN t 1 N Y
Ii 's-I
I , N 0 F , N ci EN psj N ' N
\
Ni N-\ \

air; r:6 - ON

-s. N --- '.
HN , `.. HN
I I
,- N 0 tr ..,N 0 ,,i Ni 0õ

0N1 .,..0111..7...N \ 0 N i NS1(---N. N ---HN `=...

,-N 0 \ N, ek,., N-N
Ni C
<( 173 I / 174 i 0 N, .,..0Hr--,,N9L-- 0..õ,N OH _."--, I
--, N, .-1-----6"1----:(62J-- -i . N 0 ,. N 0 el) N-N
----- KN-N
/

0....,N i OFir. ,N 40 N.., ,OH --..N \
1 I --.. N ----\ N ---HN----''''-"¨"s"-(---µ-'-r¨====
I . N 0 -1.õ...-, 0 F
N-N s. N N
N
o t-____) \ eN
,.., 177 i 178 I
o N, OH -17'N . 0..,.Nõ.
_,.0Hr5.-õ,N \ /
F
HN.'''' N --1 ,- N 0 \ri<N c tN ...,,- N 0 F
, riN
N
N
µ....---) \ o 179 i 180 I
0 N 0.,,aN ,,T,,0H(NLp Tj r,- , r HN Ny-1--- N., N ---I HN ---, 0 elµ I F
,,,,N 0 N-N
CHN..) 1-9.-''N) OFi y_12(Rs) I (RsN
0.,.....N., µ,.- .,r----- N \ 3 O,..N, ,...011r,N \
HN.,-;...õ_,,....õ_,...,,,1 N ---- I
I N 0 I HN'N,TN
- N "---õ...:,..-\ N .. -1.õõ,,, N 0 N
.....y 0__) ti) N

183 I 184 i o.xi,,..4r.,"õN 0 N OH ..9 F11:) I , 1 r N \
HNõ ' C"' N ---HN , `..
I N 0 F . N 0 =-'71'N I
'-, ) N
N

0 _ O N OH1r_.^.(,, I
HN ..N* 1 s'N. ---I ,-N 0 X%-'6N " HN "''' 1 N ---..-N 0 F

,,,,.e) e)) N
N HCOOH
r.(1 6 OH OH
187 i O N OH ,--. 188 , 1 r N \ -)Fms) -.. N -- ====. N ---HN .
.; I .,N 0 -.*Ii 0 pi 4. 4. N
.':) 1/4.N., N

0 OH .,._ ,... N
-,11 r --1,-,=;õõA,T,),..y.,N '--- HN , ''', ..--1===
N 11,.N 0 ....
--"NI .....N 0 .....,r) EN) ,õ ) "r)N'L.) -"

<1>

clit .,j \ 0 N..T ...-01-7N \
I 7 "
--, N --- ----t1,1 HN."--,.N 0 i Ns-:)/

N
<1\>

0....,N,..
Oiaccry)V.,N \
,s I r N \
N ---HN N ----1 , 1%1 ` ,,,.1 N 0 ,..s.y )(R..1.., NJ
N

0 , O....,,N, .. A ---HN-, HN''''*-----'=-,---..sy",- N
..),.. I N N -,-N 0 111 -N 0 -_, 1:-.)) I
,,õ.6) .)) 0 o 197 i 0y4.1 HO
;
HN''''''N MI;
-.,_....N 0 6.1 N -- N
y i. NO
=,''.., I:
,,õti) N) .

200 1 & 0 0 NS:f 199O 1 N
'' )-I HN
sl r4 !I
0 ),, kõN u yr 412 ) N
N
<I

201 1 202 r-r------NS:1-HN
1 HN'W'sr,i N'T)---===. .71 ...,...

....1) ....,,Nõ
c.v.,.
N

HN...,I 1 0 N OH ON (),,,N) cir,...-..,N...,01¨_,/
N--- HN "---k---r=-=
..7 y -,...
!,.....N 0 I ,,N 0 ..-.,4 =='' N -. N
II
*%. N
µ, ) õ.i;
L0) N
_ 0 205 i 206 ,7. ,,-, 0 ..:1-1 r-- N Si¨

. j...,..;:.:{1-hil -,. N ylz.---. ,s, ' ----HN HN/. N , ',-,-,1`. I , N 0 I
.,....N 0 .- IIi =='-')'- 'N
,,....,.N,, Ch(i< .) ) N
H
0 0, 207 i 208 r=11 O N N N õ0$õ,,,,N \ = , 01-14µ.=,,yiSIN \ --.. N ----HN I : ',. `,.. / N --1 HN 1 ''', ..,µ:.N 0 1 ,-N 0 te-LN
....,1) cN4 e) ;.......
N
LI
0.,..
209 i 210 0 N NP1-- r OIN:I.,....:õ..:711,--....N , t HN
, 0 --jµ.-N N ..,,-.1 N 0 ii ===,. 3 4,õ11:N

...
N
N

211 r 212 ril c I L__ .
O N
HN
1,ry ll I -,,..,1 --N 0 (...r%.51'1 N 0 ===.-I
) ) N

O N214 r õ N.SI- 0,,,...,N,N õOHrt4 \
I
-,.
HN N irk-HN'..,--,-õ,..,--,1 or..N,i(1----i , N 0 ..-..Hj ,-- N N 0 6õ.e)I,.
N tr)) <j) 0 215 ( 216 I
HN N

=-.. N ^-= y-i---HN , '`==
I ..,N 0 0 --',Nil 14 I
..(sN) ) N N

O N 0Hriirtip-, 0 N
OH(cy....p --HN N, HN
1 N.. 1 ,- N 0 F
..-N 0 iiii )(Fe.

N N

ON 0$ ...-...N \ 0,,,N,..
i N \
I ...,. I
,.. --HN 1N HN':..'--/ N

, N 0 ,..5.1,..N =.,- N 0 -=..
1 yi m ) ) N,1 ,..N
N
0+ H
0-, 0=-.

0 N 0114,4-,..N \ ON OH
I i Ta&Nc14113 'N.. N --HN -., HN 1 '===
I... N 0 F 1 ...N 0 ==",f,ii =='N
1 pp ',... N
4õ.r1;!Si N
N
N

o 223 I ! 224 I

[-,11:6 0 I
HN
' . N 0 ..- N 0 - -..sf I
,....õ.4) N
N L' <'' o N '.' 1 -N- iskirii---I ,-N 0 F

1.1 "I
i N..
O
N
N
(-I

0.,,N,, ,..0Hr.c... N \ o , ,1,1 o HN N ,...--õ.
I ..Lc N r-irNSF
----HN
F
...,..*= N 0 y 4,.. N

N e ) N

o 0...,õ..N õOH r.. .. N \ 0,....,_N,..
I
N --- HN
N --.......?
õ....? H,,,sõ, ..,.N,..
H

ON OH
HN
i I
N---- \ N -----1 N 0 I ,... N 0 ----->LN
.1kil I
ZcNj N
N Nj7 6 L,0 o 0,,N., ,-0Hr..7.õN \ 0.=..N.,.
I I
----HNN --- -,,,, N 0 ....,,,..;.N 0 -,-ti4 yi N 4õ.01:1 .) ,-- ====
e N
.5 1µ.> 0 0 ON OH ,N \ 0 N OH ,---.
I ====':.,.:,.....,,.),..,.. j.r., Fir N.õ2 \
HN
N ---HN
,..1-..õ4..-.,N 0 N 0 <51 f,õ N.....
.e.) ,tps) 6 Lõ0 .._ Embodiment 38. A pharmaceutical composition, comprising the compound of any one of embodiments 1-37 and/or a pharmaceutically acceptable salt thereof, and optionally comprising a pharmaceutically acceptable excipient.
Embodiment 39. A method of in vivo or in vitro inhibiting the activity of BTK, comprising contacting BTK with an effective amount of the compound of any one of embodiments 1-37, and/or a pharmaceutically acceptable salt thereof Embodiment 40. Use of the compound of any one of embodiments 1-37 and/or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a disease mediated by BTK or at least in part by BTK, preferably for treating or preventing cancer, an inflammatory disease or autoimmune disease, wherein the cancer is preferably solid tumor or hematologic malignancy, including lymphoma, leukemia and myeloma; the cancer is more preferably chosen from B cell malignancy, diffuse large B-cell lymphoma (DLBCL), large B-cell lymphoma (LBCL), B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, Waldenstrom macroglobulinemia, marginal zone lymphoma, Burkitt's lymphoma, non-Burkitt's highly degree B cell malignant lymphoma, extranodal marginal-zone B-cell lymphoma, small lymphotic lymphoma (SLL), lymphoblastic lymphoma, lymphocytic leukemia, myelogenous leukemia, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), human acute monocytic leukemia, acute lymphocytic leukemia (ALL), B cell acute lymphocytic leukemia (B-ALL), hairy cell leukemia, chronic lymphocytic leukemia (CLL) (such as high risk CLL), myelodysplastic syndrome, acute lymphoblastic leukemia, myeloma (such as multiple myeloma) or graft versus host disease;
and the inflammatory disease or autoimmune disease is preferably chosen from:
systemic inflammation and local inflammation, arthritis, rheumatoid arthritis, inflammation associated with immunosuppression, organ-graft refection, allergic disease, ulcerative colitis, Crohn's disease, dermatitis, asthma, lupus erythematosus, Sjogren syndrome, multiple sclerosis, sclerodetma (also referred to as systemic sclerosis), multiple sclerosis osteoporosis, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, antineutrophil cytoplasmatic antibody vasculitis, chronic obstructive pulmonary disease, psoriasis, sicca syndrome, pemphigus valgaris, diseases associated with kidney transplantation.
Embodiment 41. A method of treating or preventing a disease in a subject, comprising administering to the subject in need thereof an effective amount of the compound of any one of embodiments 1-37, and/or a pharmaceutically acceptable salt thereof, wherein the disease is a disease mediated by BTK or at least in part by BTK; the disease is preferably cancer, an inflammatory disease or autoimmune disease; the cancer is preferably solid tumor or hematologic malignancy, including lymphoma, leukemia and myeloma; the cancer is more preferably chosen from B cell malignancy, diffuse large B-cell lymphoma (DLBCL), large B-cell lymphoma (LBCL), B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, Waldenstrom macroglobulinemia, marginal zone lymphoma, Burkitt's lymphoma, non-Burkitt's highly degree B cell malignant lymphoma, extranodal marginal-zone B-cell lymphoma, small lymphotic lymphoma (SLL), lymphoblastic lymphoma, lymphocytic leukemia, myelogenous leukemia, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), human acute monocytic leukemia, acute lymphocytic leukemia (ALL), B cell acute lymphocytic leukemia (B-ALL), hairy cell leukemia, chronic lymphocytic leukemia (CLL) (such as high risk CLL), myelodysplastic syndrome, acute lymphoblastic leukemia, myeloma (such as multiple myeloma) or graft versus host disease; and the inflammatory disease or autoimmune disease is preferably chosen from: systemic inflammation and local inflammation, arthritis, rheumatoid arthritis, inflammation associated with immunosuppression, organ-graft refection, allergic disease, ulcerative colitis, Crohn's disease, dermatitis, asthma, lupus erythematosus, Sjogren syndrome, multiple sclerosis, scleroderma, multiple sclerosis osteoporosis, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, antineutrophil cytoplasmatic antibody vasculitis, chronic obstructive pulmonary disease, psoriasis, sicca syndrome, pemphigus valgaris, and diseases associated with kidney transplantation.
Embodiment 42. The compound of any one of embodiments 1-37 and/or a pharmaceutically acceptable salt thereof, for use as a medicament.
Embodiment 43. The compound of any one of embodiments 1-37 and/or a pharmaceutically acceptable salt thereof, for use in treating or preventing a disease mediated by BTK or at least in part by BTK, and preferably for use in treating or preventing cancer, an inflammatory disease or autoimmune disease, wherein the cancer is preferably solid tumor or hematologic malignancy, including lymphoma, leukemia and myeloma; the cancer is more preferably chosen from B cell malignancy, diffuse large B-cell lymphoma (DLBCL), large B-cell lymphoma (LBCL), B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, Waldenstrom macroglobulinemia, marginal zone lymphoma, Burkitt's lymphoma, non-Burkitt's highly degree B cell malignant lymphoma, extranodal marginal-zone B-cell lymphoma, small lymphotic lymphoma (SLL), lymphoblastic lymphoma, lymphocytic leukemia, myelogenous leukemia, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CM L), human acute monocytic leukemia, acute lymphocytic leukemia (ALL), B
cell acute lymphocytic leukemia (B-ALL), hairy cell leukemia, chronic lymphocytic leukemia (CLL) (such as high risk CLL), myelodysplastic syndrome, acute lymphoblastic leukemia, myeloma (such as multiple myeloma) or graft versus host disease; and the inflammatory disease or autoimmune disease is preferably chosen from: systemic inflammation and local inflammation, arthritis, rheumatoid arthritis, inflammation associated with immunosuppression, organ-graft refection, allergic disease, ulcerative colitis, Croluf s disease, dermatitis, asthma, lupus erythematosus, Sjogren syndrome, multiple sclerosis, scleroderma, multiple sclerosis osteoporosis, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, antineutrophil cytoplasmatic antibody vasculitis, chronic obstructive pulmonary disease, psoriasis, sicca syndrome, pemphigus valgaris, and diseases associated with kidney transplantation.

Embodiment 44. A pharmaceutical combination, comprising the compound of any one of embodiments 1-37 and/or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent, wherein the therapeutic agent is preferably chosen from: an anti-inflammatory agent, an immunomodulator or an anti-tumor active agent, wherein the anti-tumor active agent includes a chemotherapeutic agent, an immune checkpoint inhibitor or agonist, and a targeted therapeutic agent.
Embodiment 45. A compound of formula (VI):
Ri R31' I 1 __ : R2 ,LN 0 R3 (VI) or a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautomer thereof, wherein Xi, X2, X3, X4, RI, R., and R3 are as defined in any one of embodiments 1-34;
R31. is -CHO, -C1,3 alkyl-OH, -C1_3 alkyl-OAc, C1_3 alkyl, -C(0)-C1_3 alkyl or haloalkyl, and Rd Rd --I-BP Rd 0 -LB/ Rd 1 .
0 o \
R32 is halogen, -B(OH)2, -B(0C1_6 alkyl),, Rd or 0 Rd . and Rd is hydrogen or C1-6 alkyl.
Embodiment 46. The compound of embodiment 45, which is R31' .r....N \ R31' s.,......,./-1...i.,.
I I -....._ 0 3 ....,,../.,N 0 (V-1) (V-2) Z::::::/ R8 R32 . .,,....),...c....Tõ,.N --., R32\ N .....õ
I I

...,,s.,...õ1-N 0 -.......N 0 (v-3) . (V-4) , N..... .
R31' NN ,i. \ \
J. =I
-.õ.
R32, õ........, N R32.N.,,,...= yt \J
I r I

0 -...,..,:,.,-,,N 0 (V-5) (V-6) . , Z.----.
R31' N*1:----.'N \ / R3i= r'N'''"N \
Rrt....r.tiq --......
I I

,,..,.= N 0 ," N 0 R3 (V-7) (V-8) R31.
R31' R32 NIrsp''.. N cp.
\ 32.tr Liko N i -----.....or I R

, .3 (V-10) (V-9) or , wherein Z is N or CR7; R7 and R$ are each independently hydrogen or halogen; R9 is halogen or C1-6 alkyl;
and n is 1 or 2.
Embodiment 47. The compound of embodiment 45, which is chosen from:
,0 1.29 ,6), fic.r73:

c,,,cc....,N ...... CI N ----`s, =-..
I I ,- N 0 I
N ..N 0 ......--. N 0 OH ,Lr.,OrAcTrNi37 OAcõ,....., CINrc,Nr'N \ 91:6( riiryg-ci ..,, N -----HO..13 N ---, `,.
Co'411 I I
.,..,N 0 -, N 0 F
r:,..r.,0 .r..N ,60,i,,,,,N

,6..., r--.----N CI N --- F
`...

-,N 0 F
I
.. N 0 N- F
...õ.0 r-N \ / )) õ.,-...,, N 41t ......c.Cy 1 C1,6,..N ---- CI N ----=-.. ,..,0 :).53F
i .-N 0 N 0 CI ..,.. N ----_.- N 0 rc'rlic(FF 0 F
rN
,..,c(r)A,N
C1.6õ, N ---I CI.,,y N CI N ---, "... ----, 'N.
...N 0 I I
,.. N 0 F Br (RS) 0 N \
).....) 0 1),32- -.
õ....cilsr r? 3 ,6..rN \
ci I Z N \
CI N --- CI N ---i \ s-, i \
I I
AN 0 ,- N 0 ,- N 0 CI.6 ..,c) Nc ...õ601N 0 , µrc.Nrii.S.D
, --, `..
I I i --N 0 cL
--N 0 ,-r..;õ...,,N \ (RS) ......6..iorrs' cr,ISIL
Ci N --- CI
\ I I
i --N 0 ,- N 0 ..,61 1,:rc, (TrNS:1- Oftig., OF,167 N \
CI N --- Br N --- N ---'... , '. HO-6 i .--, i 1 fel 0 1 N 0 OH 01:21.9 F
r:,. 1,0,. N r.N
OH.,67-IN \
-B N --- HO- 4C.Li'N ' CIc ---, I ' õ-N 0 I
--N 0 õ-N 0 _60.,..r:01, ...- N 0 cN --N 0 ..,0 w.,=N 0 p =--' N.". N \
CI,y N
t---c F a 4 , i ...
' -44 0 a 4 ---e -..
i c.,...N 0 0 c.ri.....5.) 5,.0 NJ-N
CI-61r.' N \ CI
'.. , i i I
--N 0 --N 0 ,-N 0 F
' F
C1N6r:r;i:5 C1-6}3 Nr:i*
,N ----I I ,- N 0 F
,. N 0 Detailed Description of Embodiments (II):
Embodiment 1. A compound or formula (1):
Ri R4 Xr' s'X3,-=-,.
R3,õ /CY ",,NI X.;'--".
H I

Y2, ...r,..14 0 (I) or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein Xi and X7 are each independently CH or N; X3 and X4 are each independently C
or N;
Yi and Y7 are each independently CRIO or N;

R1 and R, are each independently chosen from hydrogen, deuterium, halogen, C1_6 alkyl, C2-6 alkynyl, C1-6 haloalkyl, C3-6 cycloalkyl and phenyl; or R1 and R2 together with the carbon atoms to which they are attached form the following structures:
'css) R 6 m Nis(h Y:0 /(mI (ROm --(1R6)p "1/4 (I-1) (1-2) (1-3) (1-4) or (-5) , wherein R6 is independently chosen from deuterium, halogen, C1-6 alkyl, C2..6 alkynyl, C1-6 deuteroalkyl and C1-6 haloalkyl; or two R6 together with the carbon atoms to which they are attached form 3-6 membered cycloalkyl; m is 0, 1, 2, 3 or 4; p is 1, 2, 3 or 4; Z is N or CR7;
R7 is chosen from hydrogen, deuterium, C1_6 alkyl, halogen and C1_6 haloalkyl;
R3 is hydrogen, deuterium, halogen or C1-6 haloalkyl;
R4 is hydrogen, halogen, -CN, C1-6 alkyl, C2-6 alkynyl, -(C1.3 alkyl)-0H, -(C1_3 alkyl)-0-(C1_3 alkyl), -0-(C1_3 alkyl), -CHO, -C(0)NH2, -C(0)NHCH3, -C(0)N(CH3)2 or 3-hydroxyl-oxetan-3-yl, wherein the C1_6 alkyl or C1_3 alkyl is each optionally substituted with one or more deuterium or halo;
Iii V N N
'N-1-V'* '122.cssf Cy is - U or "; wherein R11 is chosen from hydrogen, C1-6 alkyl and C3_6 cycloalkyl, wherein the C1_6 alkyl is optionally substituted with one or more deuterium or halo;
U, V and W are each independently N or CR12; R12 is hydrogen, deuterium or halogen;
R5 is hydrogen, C1..6 alkyl, -C(0)-(C1.6 alkyl), -C(0)-(C3.6 cycloalkyl), -C(0)NH-(C1-6 alkyl), -C(0)NH-(C3_6 cycloalkyl), -C(0)N(C1_6 alky1)2, phenyl, 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl, wherein the C 1-6 alkyl, C3-6 cycloalkyl, phenyl, 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl is each optionally substituted with one or more groups chosen from:
1) halogen;
2) oxo;
3) -CN;
4) C1_6 alkyl;
5) C2_6 allcenyl;
6) C2_6 alkynyl;
7) C1-6 alkoxy;
8) C1_6 haloalkyl;
9) -(C1_6 alkyl)-0H;
10) -(C1_6 alkyl)-0-(C1-6 alkyl);
11) 4-8 membered heterocyclyl optionally substituted with one or more groups chosen from: deuterium, halogen, hydroxyl, oxo, -CN, C1_6 alkyl, C1-6 haloalkyl, C3.6 cycloalkyl, C2..6 alkynyl, C1..6 alkoxy, -(C1_6 alkyl)-CN, -(C1_6 alkyl)-0-(C1-6 alkyl), -(C1_6 alkyl)-OH and 4-6 membered heterocyclyl, wherein the C1_6 alkyl, C3.6 cycloalkyl or 4-6 membered heterocyclyl is each optionally substituted with one or more groups chosen from: deuterium, halogen, -NH2, -NH(C1_6 alkyl), -N(C1.6 alky1)2 and -NH(C3_6 cycloalkyl);
12) 5-6 membered monocyclic heteroaryl optionally substituted with one or more groups chosen from: halogen, -CN, -(C1..6 alkyl)-CN, -(C1..6 alkyl)-0H, C1_6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, -(C1_6 alkyl)-0-(C1_6 alkyl), -(C1_6 alkyl)-NH2, -(C1-6 alkyl)-NH(C1_6 alkyl), -(C1..6 alkyl)-N(C1.6 alky1)2, -(C1_6 alkyl)-NH(C3-6 cycloalkyl) and 4-6 membered heterocyclyl;
13) phenyl optionally substituted with one or more groups chosen from:
halogen, -CN, -(C1_6 alkyl)-CN, -(C1_6 alkyl)-OH, C1_6 alkyl, C3-6 cycloalkyl, C1_6 alkoxy, -(C1-6 alkyl)-0-(C1..6 alkyl), -(C1..6 alkyl)-NH2, alkyl)-NH(Ci_6 alkyl), -(C1.6 alky1)2, -(C1,6 alkyl)-NH(C3,6 cycloalkyl) and 4-6 membered heterocyclyl;
14) -NRa'Ra", wherein Ra' and Ra" are each independently chosen from hydrogen, C1..6 alkyl, C3-6 cycloalkyl, -(C1.6 alkyl)-0-(C1..6 alkyl) and 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with one or more substituents of -(C1,6 alkyl)-0H;
15) -C(0)NRb'Rb", wherein Rh' and Rb" together with the N atoms to which they are attached form 4-6 membered heterocyclyl optionally substituted with one or more groups chosen from: deuterium, halogen, -OH, C1-6 alkyl, -(C1..6 alkyl)-NH,, -(C1,6 alkyl)-NH(Ci_6 alkyl), -(C1_6 alkyl)-N(Ci_6 alky1)2, -(C1.6 alkyl)-NH(C3-6 cycloalkyl), -NH2, -NH(C1..6 alkyl), -N(C1_6 alky1)2, -NH(C3_6 cycloalkyl) and -(Ci_6 alkyl)-0H; and 16) -C(0)R, wherein Rc is chosen from hydrogen, C1-6 alkyl, C2..6 aikenyl, C2-alkynyl, -(C1_6 alkyl)-OH and -(C1_6 alkyl)-0-(C1_6 alkyl);
R10 is hydrogen, deuterium, halogen, CN, C1..6 alkyl or C1-6 haloalkyl Embodiment 2. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein the compound is a compound of formula (IA):
Rfi)rn R4 x?' R5N /Cy N
I

Y2, ..1q 0 (IA) Embodiment 3. The compound of embodiment 2, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein the compound is a compound of formula (II):

CA 03171012 2022-08-12_ (R6) trn N N
kr" N
N.14 T
Y2...,..!,!N 0 (H) wherein X1 and X2 are each independently CH or N;
Y2 is CH or N;
R3 is hydrogen, deuterium, halogen or C1-6 haloalkyl;
R4 is hydrogen, halogen, -CN, C1..6 alkyl, -(C1..3 alkyl)-0H, -(C1..3 deuteroalkyl)-0H, -(C1.3 alkyl)-0-(C1-3 alkyl), -0-(C1_3 alkyl), -CHO, -C(0)NH2, -C(0)NHCH3, -C(0)N(CH3)2 or 3-hydroxyl-oxetan-3-y1;
W is N or C12.12, and R12 is hydrogen or halogen;
R5 is C1..6 alkyl, phenyl, 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl, each of which is optionally substituted with one or more groups chosen from:
1) halogen;
2) oxo;
3) -CN;
4) C1_6 alkyl;
5) C2..6 alkenyl;
6) C2_6 allcynyl;
7) C1_6 alkoxy;
8) Ci_6 haloalkyl;
9) -(Ci..6 alkyl)-0H;
10) -(C1.6 alkyl)-0-(C1.6 alkyl);
11) 4-8 membered heterocyclyl optionally substituted with one or more substituents chosen from halogen, hydroxyl, oxo, -CN, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C2..6 alkynyl, C1-6 alkoxy, -(Ci_6 alkyl)-CN, alkyl)-0-(C1-6 alkyl), -(C1.6 alkyl)-0H, 4-6 membered heterocyclyl and 4-6 membered fluoroheterocycly1;
12) 5-6 membered monocyclic heteroaryl optionally substituted with one or more substituents chosen from halogen, -CN, -(C1..6 alkyl)-CN, -(C1..6 alkyl)-0H, alkyl, C3-6 cycloalkyl, C1_6 alkoxy, -(C1.6 alkyl)-0-(C1_6 alkyl), -(C1.6 alkyl)-NH2, -(C1_6 alkyl)-NH(C1-6 alkyl), -(C1_6 alkyl)-N(C1_6 alky1)2, -(C1.6 alkyl)-NH(C3-6 cycloalkyl) and 4-6 membered heterocyclyl;
13) phenyl optionally substituted with one or more substituents chosen from halogen, -CN, -(C1.6 alkyl)-CN, -(C1.6 alkyl)-OH, C1.6 alkyl, C3-6 cycloalkyl, C1_6 alkoxy, -(C1_6 alkyl)-0(C1-6 allCY1), -(C1_6 alkyl)-NH2, -(C1-6 alkyl)-NH(C1_6 alkyl), -(C1-6 alkyl)-N(C1-6 alky1)2, -(C1_6 alkyl)-NH(C3_6 cycloalkyl) and 4-6 membered heterocyclyl;

14) -NRa'Ra", wherein R.' and Ra" are each independently chosen from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, -(Ci_6 alkyl)-0-(C1.6 alkyl) and 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with one or more substituents of -(C1_6 alkyl)-0H;
15) -C(0)NRb'Rb", wherein Rb' and Rb" together with the N atoms to which they are attached form 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with one or more substituents chosen from halogen, -OH, C1-6 alkyl, -(C1..6 alkyl)-NH2, -(C1.6 alkyl)-NH(C1 -6 alkyl), -(C1-6 alkyl)-N(Ci_6 alky1)2, -(C1_6 alkyl)-NH(C3_6 cycloalkyl) and -(C1_6 alkyl)-0H;
and 16) -C(0)R, wherein Rc is chosen from hydrogen, C1-6 alkyl, C2..6 alkenyl, C2-alkynyl and -(C1_6 alkyl)-0-(C1,6 alkyl);
R6 is halogen or C1-6 alkyl; and m is 0, 1 or 2;
preferably, W is N or CR12, and R12 is halogen;
preferably, R5 is 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl optionally substituted with one or more groups chosen from:
1) C1-6 alkyl; and 2) 4-6 membered heterocycloalkyl, which is optionally substituted with CI-6 alkyl and 4-6 membered heterocyclyl;
preferably, 5-6 membered monocyclic heteroaryl is 5 membered monocyclic heteroaryl, more preferably triazolyl;
preferably, 8-10 membered bicyclic heteroaryl is 8 membered bicyclic heteroaryl, more preferably 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl.
Embodiment 4. The compound of embodiment 2, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein the compound is a compound of formula (III):
R11 (R6)m R4 X?2.N \
HN1 -===
RI.5 0 R 3 (III) wherein X1 and X) are each independently CH or N;
Y2 is CH or N;
R3 is hydrogen, deuterium, halogen or C1-6 haloalkyl;

R4 is hydrogen, halogen, -CN, C1-6 alkyl, -(C1_3 alkyl)-0H, -(Ci_3 deuteroalkyl)-0H, -(C1.3 alkyl)-0-(Ci_3 alkyl), -O-(C1-3 alkyl), -CHO, -C(0)N H2, -C(0)NHCH3, -C(0)N(CH3)2 or 3-hydroxyl-oxetan-3-y1;
U and V are each independently chosen from N or CH;
R5 is C1_6 alkyl, phenyl, 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl, each of which is optionally substituted with one or more groups chosen from:
1) halogen;
2) oxo;
3) -CN;
4) C1_6 alkyl;
5) C2_6 allcenyl;
6) C2_6 alkynyl;
7) C1-6 alkoxy;
8) C1-6 haloalkyl;
9) -(C1_6 alkyl)-0H;
10) -(C1_6 alkyl)-0-(C1-6 alkyl);
11) 4-8 membered heterocyclyl optionally substituted with one or more substituents chosen from halogen, hydroxyl, oxo, -CN, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C2-6 alkynyl, C1-6 alkoxy, -(C1.6 alkyl)-CN, -(C1,6 alkyl)-0-(C1-6 alkyl), 4C1-6 alkyl)-0H, 4-6 membered heterocyclyl and 4-6 membered fluoroheterocycly1;
12) 5-6 membered monocyclic heteroaryl optionally substituted with one or more substituents chosen from halogen, -CN, -(C1_6 alkyl)-CN, -(C1_6 alkyl)-OH, C1-alkyl, C3-6 cycloalkyl, C1-6 alkoxy, -(C1_6 alkyl)-0-(C1_6 alkyl), -(C1_6 alkyl)-NH2, -(C1_6 alkyl)-NH(C1-6 alkyl), -(C1_6 alkyl)-N(C1-6 alky1)2, -(C1_6 alkyl)-NH(C3-6 cycloalkyl) and 4-6 membered heterocyclyl;
13) phenyl optionally substituted with one or more substituents chosen from halogen, -CN, -(C1_6 alkyl)-CN, -(C1_6 alkyl)-0H, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, -(C1_6 alkyl)-0(C1-6 alkyl), -(C1_6 alkyl)-NH2, -(C1_6 alkyl)-NH(Ci_6 alkyl), -(C1_6 alkyl)-N(Ci_6 alky1)2, -(C1_6 alkyl)-NH(C3_6 cycloalkyl) and 4-6 membered heterocyclyl;
14) -NRa'Ra", wherein Ra' and Ra" are each independently chosen from hydrogen, C1_6 alkyl, C3_6 cycloalkyl, -(C1_6 alkyl)-0-(C1_6 alkyl) and 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with one or more substituents of -(Ci_6 alkyl)-0H;
15) -C(0)NRb'Rb", wherein Rb' and Rb" together with the N atoms to which they are attached form 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with one or more substituents chosen from halogen, -OH, C1-6 alkyl, -(C1,6 alkyl)-NH2, -(C1_6 alkyl)-NH(C1_6 alkyl), -(C1-6 alkyl)-N(Ci_6 alky1)2, -(Ci_6 alkyl)-NH(C3_6 cycloalkyl) and -(C1_6 alkyl)-0H;
and 16) -C(0)R, wherein It, is chosen from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2..6 alkynyl and -(C1_6 alkyl)-0-(C1-6 alkyl);
R6 is halogen or C1-6 alkyl;

is 0, 1 or 2; and R11 is hydrogen, C1-6 alkyl or C1-6 deuteroalkyl;
preferably, U is CH, and V is N or CH; more preferably, both U and V are CH;
preferably, R11 is C1_3 alkyl, preferably methyl or ethyl, and more preferably methyl;
preferably, 5-6 membered monocyclic heteroaryl is 6 membered monocyclic heteroaryl, more preferably pyridyl, pyrazinyl and pyrimidyl;
preferably, 5-6 membered monocyclic heteroaryl is 5 membered monocyclic heteroaryl, more preferably triazolyl;
preferably, 8-10 membered bicyclic heteroaryl is 9 membered bicyclic heteroaryl, more preferably 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl;
and preferably, 4-8 membered heterocyclyl is 4-6 membered heterocyclyl, more preferably oxetanyl, azetidinyl, tetrahydropyranyl, morpholinyl, piperazinyl or tetrahydropridyl.
Embodiment 5.
The compound of any one of embodiments 1-4, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein both X1 and X2 are CH, or one of Xi and X2 is N, and the other is CH;
and preferably, both X1 and X2 are CH.
Embodiment 6.
The compound of any one of embodiments 1-5, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein Y2 is CH.
Embodiment 7.
The compound of any one of embodiments 1-6, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein R3 is hydrogen or halogen.
Embodiment 8.
The compound of any one of embodiments 1-7, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein R4 is C1_6 alkyl, -(C1_3 alkyl)-0H, -(C1.3 deuteroalkyl)-OH or -CHO;
and preferably, R4 is hydroxymethyl or hydroxy deuteromethyl.
Embodiment 9.
The compound of any one of embodiments 1-8, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastercomer or a tautomer thereof, wherein R3 is hydrogen, and R4 is -(C1-3 alkyl)-0H.
Embodiment 10.
The compound of any one of embodiments 1-9, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein R5 is chosen from AN A
Ai N
I I
eCN fp x-211n--cr(k) N¨N
R21 , R22 , R23 and R13 ;

wherein R,I is chosen from Ci.õ alkyl, C1.6 haloalkyl and -(C1_6 alkyl)-0-(C1_6 alkyl);
n is 0, 1 or 2;
R22 and R23 are each independently chosen from hydrogen, C1-6 alkyl, C1.6 haloalkyl, -(C1-6 alkyl)-0-(C1_6 alkyl), 4-6 membered heterocyclyl or -C(0)Re, and Re is chosen from hydrogen, CI .6 alkyl or -(C1..6 alkyl)-0-(C 1_6 alkyl);
A1 and A, are each independently CH or N; and R13 is chosen from:
1) hydrogen;
2) C1..6 alkyl;
3) 4-6 membered heterocyclyl optionally substituted with one or more substituents chosen from oxo, C1-6 alkyl, C1-6 alkoxy, alkyl)-0-(Ci_6 alkyl) and 4-6 membered heterocyclyl;
4) phenyl optionally substituted with one or more substituents chosen from 4-6 membered heterocyclyl;
5) -WIZ.", wherein R.' and R." are each independently chosen from hydrogen, C1-6 alkyl, -(C1_6 alkyl)-0-(C1,6 alkyl) and 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with -(Ci_6 alkyl)-0H;

and 6) -C(0)NRb'Rb", wherein Rb' and Rb " together with the N atoms to which they are attached form 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with one or more C1..6 alkyl;
Ai N
I I

preferably, R5 is R13 .
Embodiment 11. The compound of embodiment 10, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein R13 is piperazinyl optionally substituted with one or more substituents chosen from C1-6 alkyl and 4-5 membered heterocyclyl.
Embodiment 12. The compound of any one of embodiments 1-10, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein R5 is chosen from ¨I¨
AN
N
K N

A -N
AN
N tt%11 I
A2 fj" A2 1,.=,,i'i NF"."R24. N
1 R27,., N..,1 HN.,a ."--0 R26 0 R27. , R28 . R29 , L'A and . , X
AN

Rao ;
wherein R24, R24', R25, R75', R27 and R77' are each independently chosen from hydrogen, oxo and C1-6 alkyl;
R26 is C1-6 alkyl, -(c1.6 alkyl)-0-(C1..6 alkyl) or tetrahydrofuranyl;
R28 is C1_6 alkoxy; R29 is hydrogen or -(C1_6 alkyl)-OH;
R30 is C1.6 alkyl;
A1 and A, are each independently CH or N;
preferably, both A1 and Ai are CH, or one of A1 and A2 is N, and the other is CH;
and more preferably, both A1 and A2 are CH.
Embodiment 13. The compound of any one of embodiments 1-12, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a At , III 'N
A2 rj tautomer thereof, wherein R5 is chosen from 0 , whereinR24 and R74' are each independently chosen from hydrogen, oxo and C1_6 alkyl;

preferably, when R24 is C1-6 alkyl (such as C1-3 alkyl, more preferably methyl), 1*N *
AN
'--- N
iii I 11 A2 ..,/,' A2.?
'r R24TN.,.. R24/,N,,1 N-.N.J=R24' N' R24.

. is preferably o , wherein R24' is C1_6 alkyl (such as C1_3 alkyl, A..t., "-N
221?
R24.....(N
N

more preferably methyl), and more preferably o .
Embodiment 14. The compound of embodiments 12 or 13, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein R24 and R24' are each independently chosen from hydrogen and C1_6 alkyl.
Embodiment 15. The compound of any one of embodiments 10-14, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein both A1 and Ai are CH, or A, is N and A2 is CH.
Embodiment 16. The compound of any one of embodiments 1-10, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein R5 is chosen from:

.1., Ell I
..2n. 1 R24õ,..= N.
-µ,,,L. \ =s"pi NL. i 'NI " i N R24' N¨N N
/ /
R21 ,R22 and o , wherein R21 is C1-6 alkyl; R22 is chosen from hydrogen, C1-6 alkyl and 4 membered heterocyclyl; A1 and A2 are respectively CH; and R24 and R24' are each independently chosen from hydrogen and Cl_6 alkyl.
Embodiment 17. The compound of any one of embodiments 4-16, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a Ril Ril R11 Ril ON ON ON V N
I I
")s!' = cs's- -tautomer thereof, wherein li is or )2,. , wherein R11 is C1_6 alkyl or C1_6 deuteroalkyl;
preferably, R11 is C1_3 alkyl, preferably methyl or ethyl, and more preferably methyl;
and preferably, R11 is C1_3 deuteroalkyl, preferably trideuteromethyl.
Embodiment 18. The compound of any one of embodiments 4-17, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein both X1 and X2 are CH, or one of X1 and X2 is N, and the other is CH; Y2 is CH; R3 is hydrogen; R4 is -(C1_3 alkyl)-0H; U is CH, V is N or CH, and R11 is C1_3 III A ,14 A2rej N
I
N R24' alkyl; R5 is chosen from , whereinR24 and R24' are each independently chosen from hydrogen, oxo and C1-6 alkyl, both A1 and A2 are CH, or A1 is N and A, is CH; R6 is C1-6 alkyl; and m is 0 or 2.
Embodiment 19. The compound of any one of embodiments 4-18, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein both U and V are CH, and R11 is methyl.
Embodiment 20. The compound of any one of embodiments 1-19, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein R6 is C1_3 alkyl; and m is 2.
Embodiment 21. The compound of any one of embodiments 1-20, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein R6 together with the five-membered ring to which they are attached forms -Embodiment 22. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein the compound is a compound of formula (IB) \,.(R6)m R4 XX2X.--.,\
' R5N AY N A4"-".
I

Y2, 0 Yl (IB) Embodiment 23. The compound of embodiment 22, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein the compound is a compound of formula (IV):
HN U
R5 Y2.N 0 ) (IV) wherein X1 and X2 are each independently CH or N;
Y2 is CH or N;
R3 is hydrogen, deuterium, halogen or Ci_6 haloalkyl;
R4 is hydrogen, halogen, -CN, C1-6 alkyl, -(C1_3 alkyl)-0H, -(Ci_3 deuteroalkyl)-0H, -(C1.3 alkyl)-0-(C1_3 alkyl), -0-(C1_3 alkyl), -CHO, -C(0)Nfl2, -C(0)NHCH3, -C(0)N(CH3)2 or 3-hydroxyl-oxetan-3-y1;
U and V are each independently chosen from N or CH;
Z is N or CH;
R5 is C1_6 alkyl, phenyl, 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl, each of which is optionally substituted with one or more groups chosen from:
1) halogen;
2) oxo;
3) -CN;
4) C1_6 alkyl;
5) C2_6 alkenyl;
6) C2..6 alkynyl;
7) C1_6 alkoxy;
8) C1-6 haloalkyl;
9) -(Ci_6 alkyl)-0H;
10) -(Ci_6 alkyl)-0-(C1_6 alkyl);
11) 4-8 membered heterocyclyl optionally substituted with one or more substituents chosen from halogen, hydroxyl, oxo, -CN, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C2-6 al-kYnYl, C1-6 alkoxy, -(C1_6 alkyl)-CN, -(C1_6 alkyl)-0-(C1-alkyl), -(Ci_6 alkyl)-0H, 4-6 membered heterocyclyl and 4-6 membered fluoroheterocyclyl;

12) 5-6 membered monocyclic heteroaryl optionally substituted with one or more substituents chosen from halogen, -CN, -(C1_6 alkyl)-CN, -(Ci_6 alkyl)-0H, C1-alkyl, C3-6 cycloalkyl, C1-6 alkoxy, -(C1_6 alkyl)-0-(Ci_6 alkyl), -(C1.6 alkyl)-N112, -(C1_6 alkyl)-NH(C1_6 alkyl), -(C1-6 alkyl)-N(C1_6 alky1)2, -(C1_6 alkyl)-NH(C3-6 cycloalkyl) and 4-6 membered heterocyclyl;
13) phenyl optionally substituted with one or more substituents chosen from halogen, -CN, -(C1_6 alkyl)-CN, -(C1_6 alkyl)-OH, C1_6 alkyl, C3-6 cycloalkyl, C1_6 alkoxy, -(C1_6 alkyl)-0(C1_6 alkyl), -(C1_6 alkyl)-NH2, -(C1_6 alkyl)-NH(C1_6 alkyl), -(C1..6 alkyl)-N(C1_6 alky1)2, -(C1_6 alkyl)-NH(C3_6 cycloalkyl) and 4-6 membered heterocyclyl;
14) -NRa'Ra", wherein Ra' and Ra" are each independently chosen from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, -(Ci_6 alkyl)-0-(C1_6 alkyl) and 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with one or more substituents of -(C1.6 alkyl)-0H;
15) -C(0)NRb'Rb", wherein Rb' and Rb" together with the N atoms to which they are attached form 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with one or more substituents chosen from halogen, -OH, C1-6 alkyl, -(C1_6 alkyl)-NH2, -(C1_6 alkyl)-NH(Ci_6 alkyl), -(C1-6 alkyl)-N(Ci_6 alkyl)2, -(C1_6 alkyl)-NH(C3_6 cycloalkyl) and -(Ci_6 alkyl)-0H;
and 16) -C(0)R, wherein Re is chosen from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and -(C1_6 alkyl)-0-(Ci_6 alkyl);
R6 is halogen or C1-6 alkyl;
m is 0, 1 or 2; and R11 is hydrogen, C1_6 alkyl or C1-6 deuteroalkyl;
preferably, both X1 and X, are CH, or one of X1 and X2 is N, and the other is CH;
preferably, both X1 and X2 are CH;
preferably, Y2 is CH;
preferably, R3 is hydrogen or halogen;
preferably, R4 is C1-6 alkyl, -(C1_3 alkyl)-0H, -(C1_3 deuteroalkyl)-OH or -CHO; more preferably R4 is -(C1_3 alkyl)-0H;
preferably, R4 is hydroxymethyl or hydroxy deuteromethyl;
preferably, R3 is hydrogen, and R4 is -(C1_3 alkyl)-0H;
Rii Rii R11 ON.v N
jUs I
preferably, U is N or :3'2-wherein R11 is Ci.6 alkyl or C1_6 deuteroalkyl;
preferably, Z is CH;
preferably, U is CH, and V is N or CH; more preferably, both U and V are CH;
preferably, both U and V are CH, and Rii is methyl;
preferably, R11 is C1_3 alkyl, preferably methyl or ethyl, and more preferably methyl;
preferably, R11 is C1.3 deuteroalkyl, preferably trideuteromethyl;
preferably, R6 is halogen;

preferably, m is 0 or 1;
preferably, 5-6 membered monocyclic heteroaryl is 6 membered monocyclic heteroaryl, more preferably pyridyl, pyrazinyl and pyrimidyl;
preferably, 5-6 membered monocyclic heteroaryl is 5 membered monocyclic heteroaryl, more preferably triazolyl;
preferably, 8-10 membered bicyclic heteroaryl is 9 membered bicyclic heteroaryl, more preferably 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl;
and preferably, 4-8 membered heterocyclyl is 4-6 membered heterocyclyl, more preferably oxetanyl, azetidinyl, tetrahydropyranyl, morpholinyl, piperazinyl or tetrahydropyridyl.
Embodiment 24. The compound of any one of embodiments 22-23, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein Y2 is CH.
Embodiment 25. The compound of any one of embodiments 22-24, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein R5 is chosen from:
- N
7.*N Aly N
N¨N (R21) o=__ ) F(21 i422 R23 and R13 wherein R21 is chosen from C1-6 alkyl, C1-6 haloalkyl and -(C1_6 alkyl)-0-(C1-6 alkyl);
n is 0, 1 or 2;
R22 and R/3 are each independently chosen from hydrogen, C1_6 alkyl, Ci_6haloalkyl, -(C1.6 alkyl)-0-(Ci_6 alkyl), 4-6 membered heterocyclyl or -C(0)11,, and It, is chosen from hydrogen, C1_6 alkyl or -(C1_6 alkyl)-0-(Ci_6 alkyl);
A1 and A2 are each independently CH or N; and R13 is chosen from:
1) hydrogen;
2) C1_6 alkyl;
3) 4-6 membered heterocyclyl optionally substituted with one or more substituents chosen from oxo, C1-6 alkyl, C1-6 alkoxy, -(C1.6 alkyl)-0-(Ci_6 alkyl) and 4-6 membered heterocyclyl;
4) phenyl optionally substituted with one or more substituents chosen from 4-6 membered heterocyclyl;
5) -NR.'11.", wherein Ra' and R." are each independently chosen from hydrogen, alkyl, -(C1-6 alkyl)-0-(Ci_6 alkyl) and 4-6 membered heterocyclyl, wherein the membered heterocyclyl is optionally substituted with one or more -(C1_6 alkyl)-0H;
and 6) -C(0)NRt,'Rb", wherein Rb' and Rb" together with the N atoms to which they are attached form 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with one or more C1-6 alkyl;
Ai N
I

N, preferably, R5 is Ra Ra" , wherein A1 and A2 are each independently CH or N;Ra' and Ra" together with the N atoms to which they are attached form 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with one or more substituents chosen from oxo, C1-6 alkyl, C1-6 alkoxy and 4-6 membered heterocyclyl;
preferably, R13 is piperazinyl optionally substituted with one or more substituents chosen from C1_6 alkyl and 4-5 membered heterocyclyl;
preferably, R5 is chosen from:
- N
N
II A'N
R24 N R2% AN H1 A-N

1') A2.
IN R24.
N R25' R27N K> 0". N
I 0 425 OR27. R28 R29 and OWN.
N

"" R30 =
wherein R24, R24', R25, R25', R27 and 1227' are each independently chosen from hydrogen, oxo and C1-6 alkyl;
R26 is CI .6 alkyl, -(CI.6 alkyl)-0-(C1-6 alkyl) or tetrahydrofuranyl;
R28 is C1-6 alkoxy; RN is hydrogen or -(C1_6 alkyl)-0H;
R30 is C1-6 alkyl; and A1 and A,' are each independently CH or N;

A N

, rt/ rµ24 preferably, R5 is chosen from 0 , whereinR24 and R24' are each independently chosen from hydrogen, oxo and C1_6 alkyl;
more preferably, when R24 is C1_6 alkyl (such as C1_3 alkyl, more preferably methyl), N N
I I II
A2.? A2r .j.===R24' rs.24' is preferably 0 , wherein 164' is C1-6 alkyl (such as C1-3 alkyl, AN
``..1\1 A2?
more preferably methyl), and more preferably o ;
preferably, 11.14 and R24' are each independently chosen from hydrogen and CI-6 alkyl;
preferably, one of A1 and A2 is N, and the other is CH;
preferably, A1 is N and A2 is CH;
and preferably, both A1 and A, are CH.
Embodiment 26. The compound of any one of embodiments 22-25, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein both X1 and X, are CH, or one of X1 and X, is N, and the other is CH;
Y2 is CH;
R3 is hydrogen;
114 is -(C1_3 alkyl)-0H;
Z is CH;
U is CH, and V is N or CH;

.ji , ..
A N
II
A2?
N.,,,..,". ....
IN IN24' R5 is chosen from 0 , whereinR24 and R24' are each independently chosen from hydrogen, oxo and C1..6 alkyl, both A1 and A2 are CH, or A1 is N and A2 is CH;
R6 is hydrogen or halogen;
in is 0, 1 or 2; and R11 is C1_3 alkyl;
and preferably, both A1 and Ai are CH.
Embodiment 27. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, which is chosen from:
No. Structural formula No. Structural formula I I , z. I
0 . y...N.)......60,11 0,),..N..Ø..... OH
,6 NcNS
4 , HN ''' ."=== HNA"*"). I ''-- '' 1 ...N 0 ....= N 0 ei:PS --%-j/'N
I ,yli .e)o, ,o I N

N
FIN-IN--"syliN-N-g-- =---I
e(N , C --.-6 i ......; t..;1.. ,N J...........N 0 N-A
'91;=,, ---C
\r') 0 .
7 :
8 .
'N. N --- =-... ' ',, N .---HN-'"Iyµy , N 0 N N :
6, 9 1 10 t OyN.,11 =Irõ..;.,1, OH ---. sl ri.=:.N cs#N 0 1.01.14 Z..\N 0 y...cis N
( ) e)) <10 I 1 I 4 i 12 i 0....r..N 0 N
(-----N--i 1 1 -,, 01 ,.=-= Al : ,,, =-..
N N
6 µss) 13 r....N 14 '1 N = 1!.4 OH r5,--..N \ ( 0.,N,N OH.e,--. ,N 10 ----.
HN
I ; 111:1 I I
.., N 0 ,11 .., N =
N I
N

\---( 7 O

o OH _ 1 6 (----.N -1 N N , OH ....,.....-.õ cY-S
HNi "=== ',-, N..õ..+--4.---, \ , N ppi 0 >
N---' N
N--) /
17 r------N 18 f.-----N
X.,..".11,,,,c.r. HN1,-.. I -r" N - \= ,'.
.... -li.
t= (1-.LN
\ N
l 9 I i . 20 , fiN '71: : :412e-C-C-1/
6 A'' ox.........õ.....
HNNU-r.Nrcel-\rj (-1---N `0" 0 0 i.
y CM) i le N
\0/ 0 r" s'', r"" =!----'N - ' 0 N, OH
T Cyr9''; / \ .
,,,,....N 0 LoN o y C ) N

N\ 24 !
r----µ"
N, N
i il HN
N c 1 ',...
.4 0 ' .,,N 0 rPk' y ekN
N-A

N
.13>

0), r6i/N., OH....õ....g 0 N ...,OHõc,, N
r.......' Xj1-14 ---\ --HN 1 ''',. HN
' ,-N 0 N .1 . N 0 ek,14 C'e sk..i.) cNi41 ,õ..F) N

0 N.. OH _,-,õ
I re- N""9/- 0-,..eNõ, r------. \
=-, N y-4.-. 1 `-, ---HN 'j( N
1N --..
I ...0 0 1 , N 0 =="7' -...T) N-N
5)(f?
N

c 0.._,NN 11 ,OH _..... 30 .

µ-,- s - r--- N
HN( (N ---.
iN 6 eL, 1 ,N 0 N (71'14 /
Sc-F
F F
31 I - 32 , ;
0,.N.,, r,.0Hri.-=õN \ y 0 N'N OH
--(,,...N 8 (..)N ' ,,N 0 SN-N N-N
F FS
=

0 N ,,OHe...,,...N \ -I I I i HN HN
I 'N 0 .-" i ,,.N 0 \ : I
N-N N..
F F ON) ----F T
N

O *-sN I1r!..:316 \ 0 N OHr,---2(6 , I
,I,õ_ N --- -,õ N ---HN 1 -I is HN , *N-, I
N , I 0 ,-- N 0 2, .....
< ),N
i N
0õ

. .

D
O N OH t F,--,...,..
=-s. N

HN I N ---I .'''N 0 .01 '.. 1 1101 4,., N
( ) N

D
D.i,..D 40 0 I
N 0111,,--2.ir 1:61--, 39 OH r; --, 1 1 HN ...'-' , %, N ----HN
. N 0 . N 0 ( ) N

O N 01-1-, 0.,N OH,..--,,, I
-,õ N --- FIN-)Nis=-&-, Ny'67-1¨
HN , `-, ., N 0 eLti I N-N

..,.N,õ..1 \-b 0 \

õ. . N --- `-, N ---HN HN , N.
I I
.. N 0 N.1,N .-N 0 -rLN
O.,IJ y 4õ. N ,,,, N
( ) ( ) N N

0 o 0 N OH 0 N HcNSL
Ta&Nci13:1- I
rN
,..= N 0 I ,.-N 0 ..-- y I
HN0 HNo*'Gp P'l =,, I
OH

O. N,, 0 N,:. OH .====, HNN
..,..-.N 0 I
hi s-,4.,.., N 0 ,,.
yi i (:)-N----1 o N".'...) [...,_,N-..

0 N,N -OHi,,,, N \- 0TN.:01,H, I
-=-, HN , '-, HN , "=-=
I ,.. N 0 --..31 N N.,,,.-I N 0 .._,...ru =s)) ,,N....1 N
6 co I

Si 5') F

N. N --HN I
-N. : ,,, Ny::::-.
1 .. N 0 HN
I
1 ..N 0 I
0 tN) ) I N

o ON OH ,=-,..
r- - - N ON OH ,...-...,.
I i.-..irySie-===. N ---- F I
HN
I N.* HN ..."' 1 ,.., N --,.=N 0 I
==-y..-N 0 I (1.'''' N
'IV) .$) ) N

i..3.....F
0,.....õNõ,11 ,-OH .._ ._ , N \ I
0 N OH,...-..., N \
-..,......1 N 6 HN Ny.*---...,. tii ' .....N 0 ====;.,....,..11 I
4.
'.:) N

N 0Eirss" N it 0 N

., N --- `=... N ---HN
I.....N 0 F ../7 . N 0 --"---'N 1 ,....y 4.
,,õ'F) .=3)141) N
N

0 N 0Hr-,..N * 60 0 N 0Hr-,..N * F
I I
,1 , '...
I A.1 0 F --'7 .. I N 0 F
.- _ 4.
.t';1) N N
<I> 6 61 I 6/ I .
O N OHr.N --F
0 N OHr...-.......;(14 -`.. HN N --- i , ",, I .. N 0 1---.,-3 / .., N 0 Br 1 =='.... ril N 'eN)) O fisl 64 I
OH ;(1..S21--- jy, OHr,--,;&

""- -"I ="' r--- -14 \
--... N ----HN - p-(N --- HN 1 '-N
.-N 0 0 ").--.....1) ,,.. N ,,õ
.) j .1;4) N N

0x, ..,,Lsr:ii,N OH cr13 0 N OH
Ta6rNcli13-21-HN'-µ `,. N --NI , N 0 HN 1 ."-=
I
=:51"N ----====54 ., N 0 ,.....t) 1 õ.=F) ,,, N

ON 0 N1 OH ,-...
1-ki,cf.T,N ----\ N
HN 1 '''. HN"----'S'-''-'"*S'zi", N
...-N 0 ..,,...-1 N 0 I 's `..
N
N--) 0 N 011(-21153 , 0..,.N.,.. ,,OHr.7---,N \
HN-."----'."'"--"--y, N ----=-,..s.5..I N I ---N 0 o N
\
N , \ , N
N

N-1) /
/
) \
71 t---.N 72 I
N \ N,... .,OH õ.., On,..,6) rc\isrSt-N'Q,1,rrNi--\ `-. I N ---HN 1 "=-= HN 1 ''', N 0 I .. N 0 (7'LN
,1 hl-IV I
C 4, .t1)4) N
<1>
0 _ 0.,., N s.i. õOH 0 N 0Hr--,N *
I
1-iN----- N HN , '-..
I ll ,-N 0 i /
ts) ) N

0 r N\ N ___ i F 0 N 76 I
.. 0 .., I ,1 =-- r N-',. N ---- ---.. ---HNI .N. HN N , '...
,.-.N 0 ' --N 0 --.1,11 -11-''N
1 y 6 6., 't71) ''') <I
N N

OH sis5Rs) 0 N r- 0 N OHr,N
HN N N
HN

.-N 0 7, 80 0 N .,011s1:17S-N
N N
HN
-4+1 0 .õ6) Embodiment 28. A pharmaceutical composition, comprising the compound of any one of embodiments 1-27 and/or a pharmaceutically acceptable salt thereof, and optionally comprising a pharmaceutically acceptable excipient.
Embodiment 29. A method of in vivo or in vitro inhibiting the activity of BTK, comprising contacting BTK with an effective amount of the compound of any one of embodiments 1-27, and/or a pharmaceutically acceptable salt thereof.
Embodiment 30. Use of the compound of any one of embodiments 1-27 and/or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a disease mediated by BTK or at least in part by BTK, preferably for treating or preventing cancer, an inflammatory disease or autoimmune disease, wherein the cancer is preferably solid tumor or hematologic malignancy, including lymphoma, leukemia and myeloma; the cancer is more preferably chosen from B cell malignancy, diffuse large B-cell lymphoma (DLBCL), large B-cell lymphoma (LBCL), B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, Waldenstrom macroglobulinemia, marginal zone lymphoma, Burkitt's lymphoma, non-Burkitt's highly degree B cell malignant lymphoma, extranodal marginal-zone B-cell lymphoma, small lymphotic lymphoma (SLL), lymphoblastic lymphoma, lymphocytic leukemia, myelogenous leukemia, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), human acute monocytic leukemia, acute lymphocytic leukemia (ALL), B cell acute lymphocytic leukemia (B-ALL), hairy cell leukemia, chronic lymphocytic leukemia (CLL) (such as high risk CLL), myelodysplastic syndrome, acute lymphoblastic leukemia, myeloma (such as multiple myeloma) or graft versus host disease;
and the inflammatory disease or autoimmune disease is preferably chosen from:
systemic inflammation and local inflammation, arthritis, rheumatoid arthritis, inflammation associated with immunosuppression, organ-graft refection, allergic disease, ulcerative colitis, Crohn's disease, dermatitis, asthma, lupus erythematosus, Sjogren syndrome, multiple sclerosis, sclerodenna (also referred to as systemic sclerosis), multiple sclerosis osteoporosis, idiopathic thrombocylopenic purpura, autoimmune hemolytic anemia, antineutrophil cytoplasmatic antibody vasculitis, chronic obstructive pulmonary disease, psoriasis, sicca syndrome, pemphigus valgaris, diseases associated with kidney transplantation.
Embodiment 31. A method of treating or preventing a disease in a subject, comprising administering to the subject in need thereof an effective amount of the compound of any one of embodiments 1-27, and/or a pharmaceutically acceptable salt thereof, wherein the disease is a disease mediated by BTK or at least in part by MK; the disease is preferably cancer, an inflammatory disease or autoimmune disease; the cancer is preferably solid tumor or hematologic malignancy, including lymphoma, leukemia and myeloma; the cancer is more preferably chosen from B cell malignancy, diffuse large B-cell lymphoma (DLBCL), large B-cell lymphoma (LBCL), B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, Waldenstrom macroglobulinemia, marginal zone lymphoma, Burkitt's lymphoma, non-Burkitt's highly degree B cell malignant lymphoma, extranodal marginal-zone B-cell lymphoma, small lymphotic lymphoma (SLL), lymphoblastic lymphoma, lymphocytic leukemia, myelogenous leukemia, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), human acute monocytic leukemia, acute lymphocytic leukemia (ALL), B cell acute lymphocytic leukemia (B-ALL), hairy cell leukemia, chronic lymphocytic leukemia (CLL) (such as high risk CLL), myelodysplastic syndrome, acute lymphoblastic leukemia, myeloma (such as multiple myeloma) or graft versus host disease; and the inflammatory disease or autoimmune disease is preferably chosen from: systemic inflammation and local inflammation, arthritis, rheumatoid arthritis, inflammation associated with immunosuppression, organ-graft refection, allergic disease, ulcerative colitis, Crohn's disease, dermatitis, asthma, lupus erythematosus, Sjogren syndrome, multiple sclerosis, scleroderma, multiple sclerosis osteoporosis, idiopathic thrombocylopenic purpura, autoimmune hemolytic anemia, antineutrophil cytoplasmatic antibody vasculitis, chronic obstructive pulmonary disease, psoriasis, sicca syndrome, pemphigus valgaris, and diseases associated with kidney transplantation.
Embodiment 32. The compound of any one of embodiments 1-27 and/or a pharmaceutically acceptable salt thereof, for use as a medicament.
Embodiment 33. The compound of any one of embodiments 1-27 and/or a pharmaceutically acceptable salt thereof, for use in treating or preventing a disease mediated by BTK or at least in part by BTK, and preferably for use in treating or preventing cancer, an inflammatory disease or autoimmune disease, wherein the cancer is preferably solid tumor or hematologic malignancy, including lymphoma, leukemia and myeloma; the cancer is more preferably chosen from B cell malignancy, diffuse large B-cell lymphoma (DLBCL), large B-cell lymphoma (LBCL), B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, Waldenstrom macroglobulinemia, marginal zone lymphoma, Burkitt's lymphoma, non-Burkitt's highly degree B cell malignant lymphoma, extranodal marginal-zone B-cell lymphoma, small lymphotic lymphoma (SLL), lymphoblastic lymphoma, lymphocytic leukemia, myelogenous leukemia, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), human acute monocytic leukemia, acute lymphocytic leukemia (ALL), B
cell acute lymphocytic leukemia (B-ALL), hairy cell leukemia, chronic lymphocytic leukemia (CLL) (such as high risk CLL), myelodysplastic syndrome, acute lymphoblastic leukemia, myeloma (such as multiple myeloma) or graft versus host disease; and the inflammatory disease or autoimmune disease is preferably chosen from: systemic inflammation and local inflammation, arthritis, rheumatoid arthritis, inflammation associated with immunosuppression, organ-graft refection, allergic disease, ulcerative colitis, Crohn's disease, dermatitis, asthma, lupus erythematosus, Sjogren syndrome, multiple sclerosis, scleroderma, multiple sclerosis osteoporosis, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, antineutrophil cytoplasmatic antibody vasculitis, chronic obstructive pulmonary disease, psoriasis, sicca syndrome, pemphigus valgaris, and diseases associated with kidney transplantation.
Embodiment 34. A pharmaceutical combination, comprising the compound of any one of embodiments 1-27 and/or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent, wherein the therapeutic agent is preferably chosen from: an anti-inflammatory agent, an immunomodulator or an anti-tumor active agent, wherein the anti-tumor active agent includes a chemotherapeutic agent, an immune checkpoint inhibitor or agonist, and a targeted therapeutic agent.
Embodiment 35. A compound of formula (V):
Ri R31......... '.'X23,- )( , I I I __ ) R2 I

(V) or a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautomer thereof, wherein X1, X2, X3, X4, Ri, R2 and R3 are as defined in any one of embodiments 1-27;
R31 is -OH, oxo (=0), or -0-(C1_6 alkyl), and Rd 1 /0...Rd 1-13, Rd ....:_d Rt1 0 ; \
R32 is halogen, -B(OH)2, -B(0CI.6 alkyl),, Rd or 0 Rd , and Rd is hydrogen or C1-6 alkyl.
Embodiment 36. The compound of embodiment 35, which is .1-- Rs R31, rõ..õ \ Rai,N
Jz or 113 \ /
R32,0õN '--- R32 ..,.,.. N ---- R32 ,,..... N
R31 .õ..._ Ron 1N õ,--N 0 (V-1:
õ..' 0 ) (V-2) (V-3) , , R32 .,,......
or N-4) , and Z is N or CR7;R7 and Rs are each independently hydrogen or halogen; R9 is halogen or C1..6 alkyl; and n is I. or 2.
Embodiment 37. A compound, which is chosen from:
cc, ---N.

I I
..N 0 I N 0 AI 0 N-...---OH .õ,..,..x.,61--CI rN \
, \
I õ-N
,..,.6ACc7312:11-CI N ---- ..,..0Acrc--õN \
1 y '-'6:1-- HO' 1361.4 N
I I
.- N 0 .N
F
,cc.r,0 r, ... . . N ...,6 CI N - -- F
CI N ----I ...-N 0 1 ,.-N 0 F
i ..- N 0 N- F
..õ6:1õ. i }3 r;NS3,F

--N 0 .--N 0 I
.., N 0 F
,cc.10,., r.,...-;N. J.SD<F

I
.,...C.r, r'N ..,..crcr.7, CI N ---=.

c I
,- N 0 F I
-, N 0 Br (Rs) 0 (.,0 CI!
I

.- N 0 N ----I ...' ,., N 0 The various embodiments of the present invention (including the following examples) and the features of the various embodiments should be interpreted as being arbitrarily combined with each other, and the various solutions obtained by these mutual combinations are all included in the scope of the present invention, just like the solutions obtained by listing these mutual combinations specifically and individually herein, unless clearly stated otherwise in the context.
General synthetic methods The compound of formula (I) and/or a pharmaceutically acceptable salt thereof described herein can be synthesized using commercially available starting materials, by methods known in the art, or methods disclosed in the patent application. The synthetic routes shown in Scheme 1 to Scheme 2 illustrate the general synthetic methods for preparing the compounds of the present invention, and the synthetic routes shown in Scheme 3 to Scheme 6 illustrate the general synthetic methods for preparing the material 1-1 used in Scheme 1 to Scheme 2.
Scheme 1:
CHO
Ri ,-Haly-LT, Hal Ri Ri , I .-X2. OH ,X2.
CHO Xi' Xr-s.
0'4. -,, i ,) I I', , R2 Yl ...;Haiy(y.Nyx4.-Y2. ...t4 R
o R3 V2. 0.:N 0 Rs Yi Yi Ri RI R1 AO ,X2 y_. AC
Xe R2 H 1-7 _ C.ACNC2.)(4X,..1 R"N 'CY.'llat ' N

H Rs 2 Y2 :-14 0 Fts Y1 Yi Fti OH xe2.xy.s, H I
Y2. N 0 Rs Yi ( I -1) As shown in Scheme 1, a compound of formula 1-1 is reacted with a dihaloarylaldehyde compound of formula 1-2 under the catalysis of cuprous iodide to obtain a compound of formula 1-3. The carbon-nitrogen coupling reaction catalyzed by cuprous iodide is carried out under suitable conditions. The solvent used can be chosen from polar solvents such as 1,4-dioxane, DM F, etc., and the base used can be chosen from Cs2CO3, Na2CO3, K3PO4, etc.
Under suitable conditions, a compound of formula 1-4 is obtained by reducing the compound of formula 1-3.
The reducing agent used can be chosen from sodium borohydride, potassium borohydride, lithium borohydride, etc., and the solvent used can be chosen from polar solvents, such as methanol, ethanol or mixed solvent of methanol and dichloromethane. A compound of formula 1-5 is obtained by acetylating the hydroxyl on the compound of formula 1-4.
The compound of foimula 1-5 is reacted with bis(pinacolato)diboron under suitable conditions to obtain a boracic acid or boronic acid ester compound of formula 1-6. The compound of formula 1-6 is reacted with a halide of formula 1-7 by Suzuki coupling reaction under the catalysis of appropriate palladium reagent to obtain a compound of formula 1-8. Palladium catalyzed Suzuki coupling reaction is carried out under suitable conditions. The solvent used can be chosen from polar solvents such as 1,4-dioxane, DMF, THF or mixed solvent of 1,4-dioxane and water. The base used can be chosen from Cs2CO3, Na2CO3, K3PO4, etc., and the catalyst used can be chosen from Pd(dppf)C12=CH2C12, Pd(PPh3)4, Pd(OAc),), etc. A compound of thrmula (I-1) of the present invention is obtained by deacetylating the compound of formula 1-8 under appropriate alkaline conditions. The base used can be chosen from potassium carbonate, sodium carbonate, lithium hydroxide, etc., and the solvent used can be chosen from polar solvents, such as methanol, ethanol or mixed solvent of methanol and water.
Scheme 2:
aio AY,. ,Ys2.
R2.õ 2.1 130:412 CHO Xi' Xr-;
1 Ft2 R2 lialYNYX4 R6õCyTkl...,.N ______________________________ R211,0Y4Nr Rs Y2. -:h1 0 R3 Vi Y2.Vl 1.14 0 R3 Y2.
yrN
14 2-2 ( 1-1 ) As shown in Scheme 2, the compound of formula 1-3 is reacted with a boracic acid or boric acid ester of formula 2-1 by Suzuki coupling reaction under the catalysis of appropriate palladium reagent to obtain a compound of formula 2-2. Palladium catalyzed Suzuki coupling reaction is carried out under suitable conditions. The solvent used can be chosen from polar solvents such as 1,4-dioxane, DMF, THF or mixed solvent of 1,4-dioxane and water, the base used can be chosen from Cs2(203, Na2CO3, K3PO4, etc., and the catalyst used can be chosen from Pd(dppf)C12=CH2C12, Pd(PPh3)4, Pd(OAc)2, etc. Under suitable conditions, the compound of formula (I-1) is obtained by reducing the compound of formula 2-2. The reducing agent used can be chosen from sodium borohydride, potassium borohydride, lithium borohydride, etc., and the solvent used can be chosen from polar solvents, such as methanol, ethanol or mixed solvent of methanol and dichloromethane.
Scheme 3:
r r ,T,Firr* Ri Ri Ri HO R2 H2N (s 3 As shown in Scheme 3, the compound of formula 3-1 is subjected to a substitution reaction with bromoacetaldehyde diethyl acetal under suitable conditions to obtain a compound of .. formula 3-2. The base used can be chosen from cesium carbonate, etc., and the solvent used can be chosen from polar solvents such as DMF or 1,4-dioxane. The compound of formula 3-2 is hydrolyzed in an alkaline solution to obtain a compound of formula 3-3. The base used can be chosen from lithium hydroxide, potassium carbonate, sodium carbonate, etc., and the solvent used can be chosen from polar solvents, such as methanol, ethanol or mixed solvent of methanol and water. The compound of formula 3-3 is subjected to a condensation reaction with HATU and aqueous ammonia to obtain a compound of formula 3-4. The compound of formula 3-4 is subjected to ring closure in acetic acid to obtain a compound of formula 3-5.
Scheme 4:
r R
Nif*R HN ' = "' 2 As shown in Scheme 4, the compound of formula 3-2 can be subjected to a ring closure reaction with ammonium acetate in acetic acid to obtain a compound of formula 3-5.
Scheme 5:
Ri Ri H2N,N1:_: 2 R
HN 211,Y1H

= "' `-As shown in Scheme 5, the compound of formula 3-1 is reacted with 042,4-dinitrophenyl)hydroxylamine to obtain a compound of formula 5-1. The compound of formula 5-1 is subjected to a ring closure reaction with ammonium acetate in formamide solution to obtain a compound of formula 5-2.
Scheme 6:

IN2 I R2 ______ HN -As shown in Scheme 6, the compound of formula 3-1 is subjected to a substitution reaction with hydrazine hydrate to obtain a compound of formula 6-1. The compound of formula 6-1 is subjected to a ring closure reaction with triethyl orthoformate in DMF
solution to obtain a compound of formula 6-2.
The substituents of the compounds thus obtained can be further modified to provide other .. desired compounds. Synthetic chemistry transformations are described, for example, in R.
Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L.
Fieser and M.
Fieser, Fieser and Fieser 's Reagents.* Organic Synthesis, John Wiley and Sons (1994); L.
Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof.
Before use, the compound(s) of the present invention can be purified by column chromatography, high performance liquid chromatography, crystallization or other suitable methods.
Pharmceutical Compositions and Utility The compound of the present invention herein (e.g., a compound of any of the embodiments as described herein) is used, alone or in combination with one or more additional therapeutic agents, to formulate pharmaceutical compositions. A pharmaceutical composition comprises: (a) an effective amount of the compounds of the present invention; (b) a pharmaceutically acceptable excipient (e.g., one or more pharmaceutically acceptable carriers);
and optionally (c) at least one additional therapeutic agent.
A pharmaceutically acceptable excipient refers to an excipient that is compatible with active .. ingredients of the composition (and in some embodiments, capable of stabilizing the active ingredients) and not deleterious to the subject to be treated. For example, solubilizing agents, such as cyclodextrins (which form specific, more soluble complexes with the compounds of the present invention), can be utilized as pharmaceutical excipients for delivery of the active ingredients. Examples of other excipients or carries include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and pigments such as D&C Yellow #
10. Suitable pharmaceutically acceptable excipients are disclosed in Remington's Pharmaceutical Sciences, A.
Osol, a standard reference text in the art.
A pharmaceutical composition comprising a compound of the present invention herein can be administered in various known manners, such as orally, topically, rectally, parenterally, by inhalation spray, or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
A pharmaceutical composition described herein can be prepared in the form of tablet, capsule, sachet, dragee, powder, granule, lozenge, powder for reconstitution, liquid preparation, or suppository. In some embodiments, a pharmaceutical composition comprising a compound of the present invention herein is formulated for intravenous infusion, topical administration, or oral administration.
An oral composition can be any orally acceptable dosage form including, but not limited to, tablets, capsules, emulsions, and aqueous suspensions, dispersions and solutions. Commonly used carriers for tablets include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added to tablets. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions or emulsions are administered orally, the active ingredient can be suspended or dissolved in an oily phase combined with emulsifying or suspending agents. If desired, certain sweetening, flavoring, or coloring agents can be added.
In some embodiments, the compound of the present invention can be present in an amount of 1, 5, 10, 15, 20, 25, 50, 75, 80, 85, 90, 95, 100, 125, 150, 200, 250, 300, 400 and 500 mg in a tablet. In some embodiments, the compound of the present invention can be present in an amount of 1, 5, 10, 15, 20, 25, 50, 75, 80, 85, 90, 95, 100, 125, 150, 200, 250, 300, 400 and 500 mg in a capsule.
A sterile injectable composition (e.g., aqueous or oleaginous suspension) can be formulated according to techniques known in the art using suitable dispersing or wetting agents (for example, Tween 80) and suspending agents. The sterile injectable composition can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the pharmaceutically acceptable vehicles and solvents that can be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium (e.g., synthetic mono- or di-glycerides). Fatty acids, such as oleic acid and its glyceride derivatives, and natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions, can be used as sterile injectable medium. These oil solutions or suspensions can also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents.
An inhalation composition can be prepared according to techniques well known in the art of pharmaceutical formulation and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
A topical composition can be formulated in fonn of oil, cream, lotion, ointment, and the like.
Suitable carriers for the composition include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain fats or oils, animal fats and high molecular weight alcohols (greater than C12). In some embodiments, the pharmaceutically acceptable carrier is one in which the active ingredient is soluble. Emulsifiers, stabilizers, humectants and antioxidants may also be included as well as agents imparting color or fragrance, if desired.
Additionally, transdermal penetration enhancers may be employed in those topical font illations. Examples of such enhancers can be found in U.S. Patent Nos. 3,989,816 and 4,444,762.
Creams may be formulated from a mixture of mineral oil, self-emulsifying beeswax and water in which mixture the active ingredient, dissolved in a small amount of an oil, such as almond oil, is admixed. An example of such a cream is one which includes, by weight, about 40 parts water, about 20 parts beeswax, about 40 parts mineral oil and about 1 part almond oil.
Ointments may be formulated by mixing a solution of the active ingredient in a vegetable oil, such as almond oil, with warm soft paraffin and allowing the mixture to cool.
An example of such an ointment is one which includes about 30% by weight almond oil and about 70% by weight white soft paraffin.
Suitable in vitro assays can be used to evaluate the effect of the compounds of the present invention in inhibiting the activity of BTK. The compounds of the present invention can further be examined for additional effects in preventing or treating cancer by in vivo assays. For example, the compound of the present invention can be administered to an animal (e.g., a mouse model) having cancer and its therapeutic effects can be accessed. If the pre-clinical results are successful, the dosage range and administration route for animals, such as humans, can be projected.
The compound of the present invention can be shown to have sufficient pre-clinical practical utility to merit clinical trials hoped to demonstrate a beneficial therapeutic or prophylactic effect, for example, in subjects with cancer.
As used herein, the term "cancer" refers to a cellular disorder characterized by uncontrolled or disregulated cell proliferation, decreased cellular differentiation, inappropriate ability to invade surrounding tissue, and/or ability to establish new growth at ectopic sites. The term "cancer" includes, but is not limited to, solid tumors and hematologic malignancies, such as leukemia, lymphoma or myeloma. The term "cancer" encompasses diseases of skin, tissues, organs, bone, cartilage, blood, and vessels. The term "cancer" further encompasses primary cancer, and metastatic cancer, recurrent cancer and refractory cancer.
Non-limiting examples of solid tumors include pancreatic cancer; bladder cancer; colorectal cancer; breast cancer, including metastatic breast cancer; prostate cancer, including androgen-dependent and androgen-independent prostate cancer; testicular cancer; renal cancer, including, e.g., metastatic renal cell carcinoma; urothelial carcinoma; liver cancer;
hepatocellular cancer;
lung cancer, including, e.g., non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma (BAC), and adenocarcinoma of the lung; ovarian cancer, including, e.g., progressive epithelial or primary peritoneal cancer; cervical cancer; endometrial cancer; gastric cancer; esophageal cancer;
head and neck cancer, including, e.g., squamous cell carcinoma of the head and neck; skin cancer, including, e.g., melanoma and basal carcinoma; neuroendomine cancer, including metastatic neuroendocrine tumors; brain tumors, including, e.g., glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma; bone cancer; sarcoma, including, e.g., Kaposi's sarcoma; adrenal carcinoma;
mesothelial carcinoma;
choriocarcinoma; muscle carcinoma; connective tissue carcinoma; and thyroid carcinoma.
Non-limiting examples of hematologic malignancies include acute myelogenous leukemia (AML); chronic myelogenous leukemia (CML), including accelerated phase CML and CML
blastic phase (CML-BP); acute lymphocytic leukemia (ALL); chronic lymphocytic leukemia (CLL), including high risk CLL; human acute monocytic leukemia (M(5)); hairy cell leukemia;
lymphocytic leukemia; chronic lymphoid leukemia; myelogenous leukemia;
myelodysplastic syndrome or acute lymphoblastic leukemia; small lymphotic lymphoma (SLL), lymphoblastic lymphoma, and Hodgkin's lymphoma; non-Hodgkin's lymphoma (NHL); follicular lymphoma;
mantle cell lymphoma (MCL); B-cell lymphoma; T cell lymphoma; diffuse large B-cell lymphoma (DLBCL); large B-cell lymphoma (LBCL); follicular lymphoma, marginal zone lymphoma, Burkitt's lymphoma, non-Burkitt's highly degree B cell malignant lymphoma, extranodal marginal-zone B-cell lymphoma; multiple myeloma (MM); Waldenstrom macroglobulinemia; myelodysplastic syndrome (MDS), including refractory anemia (RA), refractory anemia with ring sideroblasts (RARS), refractory anemia with excess of blast (RAEB) and refractory anemia with excess blasts in transformation (RAEB-T); and myeloproliferative syndrome.
In some embodiments, hematologic malignancy is recurrent or refractory diffuse large B-cell lymphoma (DLBCL), recurrent or refractory mantle cell lymphoma, recurrent or refractory follicular lymphoma, recurrent or refractory CLL, recurrent or refractory SLL, and recurrent or refractory multiple myeloma.
The compound of the present invention can be used to achieve a beneficial therapeutic or prophylactic effect, for example, in subjects with cancer.
The compound of the present invention can be used to achieve a beneficial therapeutic or prophylactic effect, for example, in subjects with an autoimmune disease, or in subjects with inflammatory diseases.
The term "autoimmune disease" refers to a disease or disorder arising from and/or directed against an individual's own tissues or organs, or a co-segregate or manifestation thereof, or resulting condition therefrom. Examples of autoimmune diseases include, but are not limited to:
chronic obstructive pulmonary disease (COPD), allergic rhinitis, lupus erythematosus, myasthenia gravis, Sjogren syndrome, multiple sclerosis (MS), scleroderma (also referred to as systemic sclerosis), multiple sclerosis osteoporosis, arthritis (such as rheumatoid arthritis (RA), and collagen-induced arthritis), psoriasis, inflammatory bowel disease, asthma, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, antineutrophil cytoplasmatic antibody vasculitis, chronic obstructive pulmonary disease, sicca syndrome, pemphigus valgaris, and diseases associated with kidney transplantation and myeloproliferative disease, such as myelofibrosis, and post-polycythemia vera/essential thrombocytosis myelofibrosis (post-PV/ET
myelofibrosis). In some embodiment, autoimmune disease is chosen from arthritis, such as, rheumatoid arthritis (RA), collagen induced arthritis, and the like.
The term "inflammatory disease" or "inflammatory condition" refers to a pathological state that leads to inflammation, especially due to neutrophil chemotaxis. Non-limiting examples of inflammatory diseases include systemic inflammation and local inflammation, inflammation associated with immunosuppression, organ-graft refection, allergic disease, inflammatory skin disease (including psoriasis and atopic dermatitis); systemic sclerodenna and sclerosis; reactions associated with inflammatory bowel diseases (IBD, such as Crohn's disease and ulcerative colitis); ischemia reperfusion injury, including reperfusion injury of tissue caused by surgery, myocardial ischemia, such as myocardial infarction, cardiac arrest, reperfusion after heart operation and abnormal contractile response of coronary vessel after percutaneous transluminal coronary angioplasty, surgical tissue reperfusion injury of stroke and abdominal aortic aneurysm;
cerebral edema secondary to stroke; cranial injury, and hemorrhagic shock;
suffocation; adult respiratory distress syndrome; acute lung injury; :Behcet's disease;
dermatomyositis;
polymyositis; multiple sclerosis (MS); dermatitis; meningitis; encephalitis;
uveitis; osteoarthritis;
lupus nephritis; autoimmune disease such as rheumatoid arthritis (RA), Sjorgen's syndrome, and vasculitis; diseases involving leukopedesis; septicemia or central nervous system (CNS) inflammatory disease secondary to trauma, and multiple organ injury syndrome;
alcoholic hepatitis; bacterial pneumonia; antigen-antibody complex mediated disease, including glomerulonephritis; pyaemia; sarcoidosis; irnrnunopathologic responses to tissue/organ transplantation; lung inflammation, including pleurisy, alveolitis, vasculitis, pneumonia, chronic bronchitis, bronchiectasia, diffuse panbronchiolitis, hypersensitivity pneumonitis, idiopathic pulmonary fibrosis (IPF), cystic fibrosis, etc. Preferably indications include, but are not limited to, chronic inflammation, autoimmune diabetes, rheumatoid arthritis (RA), rheumatoid spondylitis, gouty arthritis and other arthrosis conditions, multiple sclerosis (MS), asthma, systemic lupus erythematosus, adult respiratory distress syndrome, Behcet's disease, psoriasis, chronic pulmonary inflammatory disease, graft versus host reaction, Crohn's disease, ulcerative colitis, inflammatory bowel disease (IBD), Alzheimer's disease and pyresis, and any diseases associated with inflammation and related conditions.
In addition, the compounds of the present invention (e.g., a compound of any of the embodiments as described herein) can be administered in combination with additional therapeutic agents for the treatment of diseases or disorders described herein, such as cancer, an inflammatory disease or autoimmune disease. The additional active ingredients may be administered separately with the compound of the present invention or included with such an ingredient in a pharmaceutical composition according to the disclosure, such as a fixed-dose combination drug product. In some embodiments, additional active ingredients are those that are known or discovered to be effective in the treatment of diseases mediated by BTK or at least in part by BTK, such as another BTK inhibitor or a compound active against another target associated with the particular disease. The combination may serve to increase efficacy (e.g., by including in the combination a compound potentiating the potency or effectiveness of the compound of the present invention), decrease one or more side effects, or decrease the required dose of the compound of the present invention.

In some embodiments, the compounds of the present invention (such as any compound herein) can be administered in combination with additional therapeutic agents, such as anti-inflammatory agents, immunomodulators or anti-tumor active agents, wherein the anti-tumor active agents include chemotherapeutic agents, immune checkpoint inhibitors or agonists, and targeted therapeutic agents. The term "anti-tumor active agent" as used herein refers to any agent that is administered to a subject suffering from cancer for the purposes of treating the cancer, such as a chemotherapeutic agent, an immune checkpoint inhibitor or agonist, and a targeted therapeutic agent.
Non-limiting examples of chemotherapeutic agents include topoisomerase I
inhibitors (e.g., irinotecan, topotecan, camptothecin and analogs or metabolites thereof, and doxorubicin);
topoisomerase 11 inhibitors (e.g., etoposide, teniposide, mitoxantrone, idarubicin, and daunorubicin); alkylating agents (e.g., melphalan, chlorambucil, busulfan, thiotepa, ifosfamide, carmustine, lomustine, semustine, streptozocin, decarbazine, methotrexate, mitomycin C, and cyclophosphamide); DNA intercalators (e.g., cisplatin, oxaliplatin, and carboplatin); and free radical generators such as bleomycin; nucleoside mimetics (e.g., 5-fluorouracil, capecitabine, gemcitabine, fludarabine, cytarabine, azacitidine, mercaptopurine, thioguanine, pentostatin, and hydroxyurea); paclitaxel, docetaxel, and related analogs; vincristine, vinblastin, and related analogs; thalidomide and related analogs (e.g., CC-5013 and CC-4047).
Non-limiting examples of immune checkpoint inhibitors or agonists include PD-1 inhibitors, for example, anti-PD-1 antibodies, such as pembrolizumab and nivolumab; PD-Li inhibitors, for example, anti-PD-L1 antibodies, such as atezolizumab, durvalumab, and avelumab; CTLA-4 inhibitors, such as anti- CTLA-4 antibody, for example ipilimuniab; and BTLA
inhibitors, LAG-3 inhibitors, TIM3 inhibitors, TIGIT inhibitors, VISTA inhibitors, OX-40 agonists, and the like.
Targeted therapeutic agents include various small molecule or macromolecular targeted therapeutic agents, and non-limiting examples thereof include: protein tyrosine kinase inhibitors (such as imatinib mesylate and gefitinib); proteasome inhibitors (such as bortezomib); NF-KB
inhibitors, including IKB kinase inhibitors; P131(8 inhibitors; SYK
inhibitors; Bc12 inhibitors;
antibodies that bind to proteins overexpressed in cancer to down-regulate cell replication, such as anti-CD20 antibody (such as ritwcimab, ibritumomab tiuxetan, and tositumomab), anti-Her2 monoclonal antibody (trastuzumab), anti-EGFR antibody (cetuximab) and anti-VEGFR antibody (bevacizumab); anti-angiogenic drugs, such as lenalidomide; and other protein or enzyme inhibitors, these proteins or enzymes are known to be upregulated, overexpressed or activated in cancers, and the inhibiting on them can down-regulate cell replication.
EXAMPLES
The examples below are intended to be purely exemplary and should not be considered to be limiting in any way. Efforts have been made to ensure the accuracy with respect to numbers used (for example, amounts, temperature, etc.), but those skilled in the art should understand that some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in degrees Centigrade, and pressure is at or near atmospheric. All MS data were determined by Agilent 6120 or Agilent 1100. All NMR data were generated using a Varian 400 MR machine. All reagents and materials, except synthesized intermediates, used in the present invention are commercially available. The reference GDC-0853 (fenebrutinib) was purchased from Shanghai Linkchem Medical Technology Co., Ltd. All compound names except the reagents are generated by Chemdraw 16Ø
If there is any atom with empty valence(s) in any one of the structures disclosed herein, the empty balance(s) is (are) the hydrogen atom(s) which is (are) omitted for convenience purpose.
In the present application, in the case of inconsistency of the name and structure of a compound, when the two of which are both given for the compound, it is subject to the structure of the compound, unless the context shows that the structure of the compound is incorrect and the name is correct.
In the following examples, the abbreviations are used:
Ac Acetyl AcOK Potassium acetate BINAP Bis-(diphenylphosphino)-1,1'-binaphthyl CDI N,N'-carbonyldiimidazole CD3OD Deuterated methanol DCM Di chloromethane DIAD Diisopropyl azodicarboxylate DIEA N,N-diisopropylethylamine DMF N,N-dimethylformamide DM SO Dimethyl sulfoxide DMSO-d6 Deuterated dimethyl sullbxide EA/Et0Ac Ethyl acetate Et3N Triethylamine Et0H Ethanol Gram HATU 2-(7-azabenzotriazole)-N,N,N',M-tetramethyluronium hexafluorophosphate HMDSLi Lithium hexamethyldisilazide Liter Mole/liter Me0H Methanol mg Milligram m L Milliliter mmol Millimole mol Mole NBS N-bromosuccinimide Pd2(dba)3 Tris(dibenzylidene acetone)dipal ladium Pd(dppf)C12 CH2C12 [1,1'-bis(diphenylphosphino) ferrocene ]palladium dichloride dichloromethane complex PE Petroleum ether TF A Trifluoroacetic acid THF Tetrahydrofuran Xphos 2-dicyclohexylphosphine-2',4',6'-triisopropyl biphenyl Xant-phos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene Example 1 Synthesis of Compounds Intermediate 1-1 4-chloro-2-(1-oxo-1,6,7,8-tetrahydro-2H-cyclopenta[4,51pyrrolo[1,2-alpyrazin-2-yl)nicotinaldehyde CI
Step 1 0J 0 Step 2 0, \ 9 Step 3 L
Step 4 N `co Step 6 N
(r)¨{
- N 0 --,o /0 KrNH2 >====i Step 6 N' 0 Step 7 \ Step 8 HN
/c) Nyi---4..,-/
I, Step 1: 2-chlorocyclopentan-1-ene-1-carbaldehyde At 0-5 C, phosphorus oxychloride (4.45 mL, 47.7 mmol) was dropwise added to DMF (4.6 mL, 59.6 mmol) under nitrogen. The reaction solution was stirred at 0-5 C for 10 minutes, and then further stirred at room temperature for 15 minutes. Cyclopentanone (2.5 g, 29.8 mmol) was dropwise added to the above-mentioned reaction solution at 0-5 C, which was reacted at room temperature for 1 hour, and then poured into ice water (the pH value was adjusted to 5 with an aqueous sodium carbonate solution), and 100 mL of water was added. The reaction solution was extracted with petroleum ether/ethyl acetate = 10/1(100 mL x 2), and the organic phase was collected and combined, washed with saturated brine (100 mL), dried with anhydrous sodium sulfate, and concentrated to give the target product (2.4 g, yield 62%), which was directly used in the next step.
Step 2: (E)-3-(2-chlorocyclopenta-1-ene-1-yl)ethyl acrylate Under nitrogen, 2-chlorocyclopentan-1-ene-1-carbaldehyde (2.4 g, 18.4 mmol) and ethoxy(formylmethylene)triphenylphosphorane (6.4 g, 18.4 mmol) were placed in dichloromethane (30 mL), which was reacted at the reflux temperature for 6 hours. The reaction solution was concentrated in vacuum under reduced pressure, and the resulting residue was purified with silica gel column chromatography (petroleum ether/ethyl acetate) to give the target product (3.3 g, yield 89%). [M+H] 201.1 Step 3: Ethyl 1,4,5,6-tetrahydrocyclopentadienolbjpyrrole-2-carboxylate Under nitrogen, to a solution of (E)-3-(2-chlorocyclopenta-1-ene-1-y1)ethyl acrylate (3.3 g, 16.5 mmol) in DMSO (20 mL) was added sodium azide (1.6 g, 24 mmol), which was reacted at 65 C for 16 hours. Water (200 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL x 2). The organic phase was collected and combined, and concentrated in vacuum under reduced pressure, and the resulting residue was purified with silica gel column chromatography (petroleum ether/ethyl acetate) to give the target product (700 mg, yield 24%). [M+H] 180.1. 1HNMR (400 MHz, CDC13): ö 8.81 (s, 1H), 6.65 (s, 1H), 4.30-4.26 (m, 2H), 2.75-2.55 (m, 4H), 2.42-2.40 (m, 2H), 1.35-1.31 (in, 3H).
Step 4: Ethyl 1-(2,2-diethoxyethyl)-1,4,5,6-tetrahydrocyclopentadieno[b]pyrrole-2-carboxylate To a solution of ethyl 1,4,5,6-tetrahydrocyclopentadieno[b]pyrrole-2-carboxylate (700 mg, 3.9 mmol) in DMF(5 mL) was added cesium carbonate (3.2 g, 9.7 mmol) and bromoacetaldehyde diethyl acetal (1.55 g, 7.8 mmol), which was reacted at 100 C for 16 hours.
Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL x 21). The organic phase was collected and combined, and concentrated in vacuum under reduced pressure, and the resulting residue was purified with silica gel column chromatography (petroleum ether/ethyl acetate) to give the target product (1.0 g, yield 92%).
[M+Na] 318.1 Step 5: 1-(2,2-diethoxyethyl)-1,4,5,6-tetrahydrocyclopentadieno[b]pyrrole-2-carboxylic acid To a solution of ethyl 1-(2,2-diethoxyethyl)-1,4,5,6-tetrahydrocyclopentadieno[b]pyrrole-2-carboxylate (1.0 g, 3.6 mmol) in ethanol (10 mL) and water (10 mL) was added lithium hydroxide monohydrate (650 mg, 14.4 mmol), which was reacted at 80 C for 12 hours. Ethanol was removed in vacuum under reduced pressure, and the pH was adjusted to 5-6 with concentrated hydrochloric acid, and water (20 mL) was added. The reaction solution was extracted with ethyl acetate (20 mL x 2), the organic phase was collected and combined, dried with anhydrous sodium sulfate, and concentrated to give the target product (800 mg, yield 83%).
[M-HT 266.1 Step 6: 1-(2,2-diethoxyethyl)-1,4,5,6-tetrahydrocyclopentadieno[b]pyrrole-2-carboxamide At 0-5 C, under nitrogen, to a solution of 1-(2,2-diethoxyethyl)-1,4,5,6-tetrahydrocyclopentadieno[b]pyrrole-2-carboxylic acid (800 mg, 3 mmol) in DMF(5 mL) was added triethylamine (0.84 mL, 6 mmol) and HATU (1.7 g, 4.5 mmol). After reacting at room temperature for 30 minutes, the reaction solution was poured into concentrated aqueous ammonia (20 mL) and stirred for 10 minutes. Water (20 mL) was added, the reaction solution was extracted with dichloromethane (20 mL x 2), and the organic phase was collected and combined, and concentrated to give the target product (1.0 g, yield 125%), which was directly used in the next step.
Step 7: 7,8-dihydro-2H-cyclopenta[4,51pyrrolo[1,2-alpyrazin-1(611)-one 1-(2,2-diethoxyethyl)-1,4,5,6-tetrahydrocyclopentadieno[b]pyrrole-2-carboxamide (1.0 g, 3.75 mmol) was dissolved in acetic acid (10 mL), which was reacted at 100 C
for 4 hours (acetic acid was removed in vacuum under reduced pressure, the pH value was adjusted to 8 with aqueous ammonia), water (20 mL) was added, and the mixture was extracted with dichloromethane (20 mL x 2). The organic phase was collected and combined, and concentrated in vacuum under reduced pressure, and the resulting residue was purified with silica gel column chromatography (dichloromethane/methanol) to give the target product (600 mg, yield 92%).
[M+H] 175.1 Step 8: 4-ehloro-2-(1-oxo-1,6,7,8-tetrahydro-2H-cyclopenta[4,51pyrrolo(1,2-alpyrazin-2-yl)nicotinaldehyde Under nitrogen, to a solution of 7,8-dihydro-21/-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(61-0-one (600 mg, 3.5 mmol) and 2-bromo-4-chloronicotinaldehyde (1.1 g, 5.1 mmol) in 1,4-dioxane (30 mL) was added cuprous iodide (665 mg, 3.5 mmol), 4,7-dimethoxy-1,10-phenanthroline (580 mg, 2.45 mmol) and cesium carbonate (2.2 g, 7.0 mmol). The mixture was reacted at 90 C for 12 hours, and then cooled to room temperature. The mixture was concentrated in vacuum under reduced pressure, and the resulting residue was purified with silica gel column chromatography (petroleum ether/ethyl acetate) to give the target product (400 mg, yield 37%). [M+H] 314.0 The intermediates in the following table were prepared with corresponding materials and reagents according to the preparation steps of intermediate I-1:
Intermedi LC-MS
Structural formula ate [M+Hr 1-55 342.0 I I

r/N-N
1-64 343.0 N
Nt.
1-77 rc 328.0 I

1-79 342.0 I I
\ 0 1-80 330.0 I I

r;---srri43:1 356.1 ,N
I I

\ (RS) =
1-90 328.1 I I

r-5:7"N \ (RS) 1-95 341.8 I I

o 1-96 338.0 I I

r7-NN \ 386.0, 388.0 Intermediate 1-2 (54(54(2S,5R)-2,5-dimethy1-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-1-methyl-6-oxo-1,6-dihydropy rid in-3-yl)boracic acid Boy c, Step 1 N
tHS) CS)i Step 2 N NO2 "N-:

0-"A (a step 3 N esf Step 4 m 40.
N .\NO2 N N112 0*. Of:j ,OH
HNA,-,j.sr HN
OH' lN
Step 5 Step 6 =,.õ N.

Step 1: 1-butyl (2R,5S)-2,5-dimethy1-4-(6-nitropyridin-3-yl)piperazin-l-carboxylate Under nitrogen, to a solution of 5-bromo-2-nitropyridine (7.0 g, 32.7 mmol) and 1-butyl (2R,5S)-2,5-dimethylpiperazin-1-carboxylate (10.0 g, 49.0 mmol) in 1,4-dioxane (150 mL) was added Xant-phos (3.8 g, 0.64 mmol), Pd2(dba)3 (3.0 g, 0.32 mmol) and cesium carbonate (21.3 g, 65.3 mmol). The mixture was reacted at 100 C for 16 hours, and then cooled to room temperature. The reaction solution was concentrated in vacuum under reduced pressure, and the resulting residue was purified with silica gel column chromatography (petroleum ether/ethyl acetate) to give the target product. [M+H] 337.1 Step 2: (2R,5S)-2,5-dimethy1-1-(6-nitropyridin-3-yl)piperazine Under nitrogen, to a solution of 1-butyl (2R,5S)-2,5-dimethy1-4-(6-nitropyridin-3-yl)piperazin-1-carboxylate obtained from step 1 in methanol (10 mL) was added concentrated hydrochloric acid (3 mL). The reaction was stirred at room temperature for 30 minutes, and concentrated in vacuum under reduced pressure, and the resulting residue was purified with silica gel column chromatography (methanol/water) to give the target product (3.3 g, two-step yield 43%). [M+H] 237.1 Step 3: (2S,5R)-2,5-dimethy1-1-(6-nitropyridin-3-y1)-4-(oxetan-3-yl)piperazine Under nitrogen, to a solution of (2R,5S)-2,5-dimethy1-1-(6-nitropyridin-3-yl) piperazine (3.3 g, 14.0 mmol) and oxetan-3-one (3.1 g, 42.0 mmol) in methanol (20 mL) was added zinc chloride (5.7 g, 42.0 mmol) and sodium cyanoborohydride (2.6 g, 42.0 mmol).
The reaction was .. stirred at 50 C for 5 hours, and concentrated in vacuum under reduced pressure, and the resulting residue was purified with silica gel column chromatography (methanol/water) to give the target product (3.3 g, yield 80%). [M+Hr 293.1 Step 4: 54(2S,5R)-2,5-dimethy1-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-amine At room temperature, to a mixture of (2S,5R)-2,5-dimethy1-1-(6-nitropyridin-3-y1)-4-(oxetan-3-yl)piperazine (3.3 g, 11.3 mmol) and 10% palladium-carbon (with 50%
water, 400 mg) in methanol (50 mL) was introduced with hydrogen, which was reacted at room temperature for 12 hours. The reaction solution was filtered, and the filtrate was collected, and concentrated in vacuum under reduced pressure to give the target product (2.94 g, yield 99%), which was directly used in the next step. [M+H] 263.1 Step 5: 5-bromo-34(54(25,5R)-2,5-dimethy1-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-1-methylpyridin-2(1H)-one Under nitrogen, to a solution of 54(2S,5R)-2,5-dimethy1-4-(oxetan-3-yppiperazin-1-yppyridin-2-amine (2.94 g, 11.2 mmol), 3,5-dibromo-1-methylpyridin-2(110-one (3.0 g, 11.2 mmol) in 1,4-dioxane (150 mL) was added Xant-phos (325 mg, 0.56 mmol), Pd2(dba)3 (515 mg, 0.56 mmol) and cesium carbonate (7.3 g, 22.5 mmol). The mixture was reacted at 100 C for 16 hours, and then cooled to room temperature. The reaction solution was concentrated in vacuum under reduced pressure, and the resulting residue was purified with silica gel column chromatography (methanol/dichloromethane) to give (4.7 g, yield 93%). [M+H]
448.1, 450.0 Step 6: (54(54(25,5R)-2,5-dimethy1-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)boracic acid Under nitrogen, to a solution of 5-bromo-34(5-02S,5R)-2,5-dimethy1-4-(oxetan-3-yl)piperazin-1-y1)pyridin-2-y1)amino)-1-methylpyridin-2(1H)-one (4.7 g, 10.5 mmol), bis(pinacolato)diboron (13.3 g, 52.4 mmol) in 1,4-dioxane (200 mL) was added Xphos (500 mg, 1.05 mmol), Pd2(dba)3 (480 mg, 0.52 mmol) and potassium acetate (3.0 g, 31.4 mmol). The mixture was reacted at 60 C for 16 hours, and then cooled to room temperature.
The reaction solution was filtered, and the filtrate was collected and concentrated in vacuum under reduced pressure, and the resulting residue was purified with silica gel column chromatography (methanol/water) to give the target compound (2.3 g, yield 53%). [M+H] 414.2 The intermediates in the following table were prepared with corresponding materials and reagents according to the preparation steps of intermediate 1-2:
Structural LC-MS Structural LC-MS
+ Intermediate intermediate formula I M+111 formula 1M+111+

I I
HN-)JCI HN3L Br ....,i) 405.1 I-11 i 420.1, N 422.1 N N
6 ) 0......y.N,,i r--- --N
,),..õ), iq HN...'s*--"'Br N
HN,k.N...,1,a sy 434.1, N 346.0 436.1 rsi ) N--) N
6 d 1 , 0N,z NN HNBr HNCI : 434.0, N
y1-18 304.1 1-35 pl c...,..N..) 436.0 N
Ni /

0,, _A
=====- --,, HNB"LiZ<I I .
' 0N,.., ..zy 482.3 1-56 HN''.-------.'13,0H
16 1 . 1 OH
) )"N
<-1) __.
I
0..s.õ.N...r I HN'....--µ-'I
B,.OH

=='' '.. 1N OH
,... I
,H i 1-57 HN 246.0 1-65 -.. 414.2 OH
").'N
N

I
0,N
HN,.1 W I
Aj-= 0 0...N..,1 '\x!
AiL 1-67 \ ,N 61c - 472.2 1-69 HN Er0 ..... 332.1 t4 .-.L.Ni O-N-) ik-ni Bad i Ot..,N,.
1 HN 1? ....,<.
ON..,1 AjL ...0 ,r) 1-73 HN E 76 482.2 L1.,.. 327.1 N
D4 Dt ID I

O,.,t4,1 HN,=:-...õ..õ1...B
,K. .
HN q....K 0 OH
=-',1 \ N, 1-78 1 485.3 1-134 348.0 ) --?
N

\

I
Or..N.,1 I
HN.s.=-=.)..13,..OH 0===- N`, 6H Hiµr-^Us'Er 346.0 1-144 ,4< 373.0 N
\ N' N----) 0 ----) d0 I ' 0 -,....,. N .,..
I
HN
0'-.:=,- N`--,, 1 =-""-j. N 6---HIN''''Bn `-, 439.0 el=-1-145 345.0 1-146 -,. 6)--- -N-N
K' N

I I
0õ. Nits1 B4OH AN,õjk. ..0 HN HN B .....<
N H
i 6 =''tisl y I
1-162 414.0 1-166 496.2 ,,,..chl,, (S)(R) ......N) 0, N.,, I
HN '-13-1.(), NH2 -----'4LN 1 ,,,i) 1-167 496.2 1-168 293.1 4, . e )) N
N gioc ! ------F, 1-169 ,,õ.4) 266.1 1-170 249.1 N \¨N
6 bi NH2 NH2 . ______ 1-171 ,,,,. NH
223.1 1-172 HN.,1 267.0 ,r..s.N) NH
6 OH /'\

-!1"N NH2 ii I-173 ,,õ.4) 267.0 1-174 -...),... ,N
,,õ 249.1 N .e1) rIN-1 0 OH OH
, ______ II II
1-175 t,õ .)N1) 250.2 1-176 ,õ,õ,(N
(s) j 264.2 N N

_ II 4)P1 -NI) ( ) 236.0 1-178 N
,-- ---. 220.1 N

, .....i.) y 1-179 H,f,skrj 247.0 1-180 261.1 N H N
<1 6 Nyi , ,....i) 1-181 235.1 1-182 N 234.1 N,.
C AAS) (0) ' y yi 0 ) 263.1 1-184 N
, 247.1 , =.-' '-=
NH2 ,, I n =j-LNI 6----c -=ky.) 1-185 249.1 1-186 483.3 4,õ Isi,,.
..,..c.SI) N ) Lõ0 ND
0 , , Intermediate 1-3 5-bromo-3-((5-ethyl(2-methoxyethyl)amino)pyridin-2-371)amino)-1-methylpyridin-2(1R)-one Step Step 2 N, I I
.0 o,N2j, N HNx Br Step 3 Step 4 Step 1: N-(2-methoxyethyl)-6-nitropyridin-3-amine To a solution of 5-fluoro-2-nitropyridine (4.26 g, 30 mmol) and 2-methoxyethylamine (2.48 g, 33 mmol) in DMSO (30 mL) was added triethylamine (21.2 g, 210 mmol). The mixture was reacted at 100 C for 4 hours, and then cooled to room temperature. The reaction solution was poured into water (200 mL), and extracted with ethyl acetate (200 mL x 2). The organic phase was collected and combined, and concentrated in vacuum under reduced pressure, and the resulting residue was purified with silica gel column chromatography (methanol/dichloromethane) to give the target product (5.92 g, yield 100%).
[M+H] 198.1 Step 2: N-ethyl-N-(2-methoxyethyl)-6-nitropyridin-3-amine At 0-5 C, under nitrogen, to a solution of N-(2-methoxyethyl)-6-nitropyridin-3-amine (986 mg, 5.0 mmol) in DMF (10 mL) was added 60% sodium hydride (mineral oil dispersion) (240 mg, 6.0 mmol), and stirred at this temperature for 1 hour. Bromoethane was added to the mixture, and the mixture was reacted at 60 C for 2 hours, and cooled to room temperature. The reaction solution was concentrated in vacuum under reduced pressure, and the resulting residue was dissolved in dichloromethane (100 mL), and washed with water (50 mL). The organic phase was collected, and concentrated in vacuum under reduced pressure to give the target product (1.13 g, yield 100%), which was directly used in the next step. [M+H] 226.1 Step 3: N5-ethyl-N5-(2-methoxyethyl)pyridin-2,5-diamine At room temperature, to a mixture of N-ethyl-N-(2-methoxyethyl)-6-nitropyridin-3-amine (1.13 g, 5.0 mmol) and 10% palladium-carbon (with 50% water, 200 mg) in methanol (20 mL) was introduced with hydrogen, which was reacted at room temperature for 16 hours. The reaction solution was filtered, and the filtrate was collected and concentrated in vacuum under reduced pressure, and the resulting residue was purified with silica gel column chromatography (methanol/water) to give the target product (875 mg, yield 90%). [M+H] 196.1 Step 4: 5-bromo-3-((5-ethyl(2-methoxyethyl)amino)pyridin-2-y1)amino)-1-methylpyridin-2(111)-one Under nitrogen, to a solution of 1V5-ethyl-N5-(2-methoxyethyl)pyridin-2,5-diamine (195 mg, 1.0 mmol), 3,5-dibromo-l-methylpyridin-2(1H)-one (267 mg, 1.0 mmol) in 1,4-dioxane (5 mL) was added Xant-phos (58 mg, 0.1 mmol), Pd2(dba)3 (92 mg, 0.1 mmol) and cesium carbonate (652 mg, 2.0 mmol). The mixture was reacted at 100 C for 16 hours, and then cooled to room temperature. The reaction solution was concentrated in vacuum under reduced pressure, and the resulting residue was purified with silica gel column chromatography (methanol/dichloromethane) to give the target product (257 mg, yield 67%).
[M+Hr 381.1, 383.1 The intermediates in the following table were prepared with corresponding materials and reagents according to the preparation steps of intermediate 1-3:
Structural LC-MS Structural LC-MS
Intermediate , Intermediate formula MAI] = formula EM+Hr 0 Al I
====
HNBr 312.0, HN.,A.CI
1-8 1-9 313.9 N
269.0 ek N c51.¨
N-N N-N
-----c -----c I
IN,..N
HN Br 0 NI
%-- -, -='... fj1 HN
1 N 436.1, 379.0, õ
-,, 1-10 *-'1' 4 438.1 - . 381.0 Iii.rsj 1-12 y ) ) 40, N e) 0,_ rN
0 N N , z= N
=-=` '-, \-- --,, H N Br 352.0, HNCI

N 1-19 390.0 \ N, 354.0 Ni 0 > FLN
N¨/ N---) / Boci r-----N,i f----N
N N N.,N.,.
-..
I
HNCI HINCI
1-20 278.0 1-21 () 264.0 NN eLN
N-N N-N
---- c r---1 0..,NI N N
,.(.. *
HN N Br HN --s*----C1 ==-)1 =-"::-LN
I 434.9, y 400.1 .
4,, 4õ
.F) 4369 .6) N N

I F
0*,N, ----( HN-`sj.CI Nf, N
,,_ I
HNBr -'. .1)4 I -='11 461.1;
4,3 463.1 'F 391.1 1-25 1 ) e) ) N
N

1 , ON- 0,.N..t4 HN" -=:-"- 'Br 298.0, 300.0 N

255.0 Ii (-%1'N
N-N N-N
c c I
ON
HN)k...)-.Br I
0.,,N
" 392.1, HN..)1.Br 284.0, 394.1 (Isl 286.0 e .$) ) /
N-N
N
I
I
Co..,N.
I
HNk,Br X ,./., 1,LN-N
1-30 HN a 241.0 1-36 ---..y i 365.0, 367.0 e(N
N-N A
/
Y
0, (:)Nõ, I HN)-k.).Br ==-=" -,, 245.0, 365.0, 1-40 ..., i 1-41 .--,,... ji HINF----Br 247.0 1 367.0 ..L.
N
,- ,,,----µ
\--a 1- '--Si"--/ \ I
0y,N.N CoN
HNAõ-.),.Br --0 367.0, 1-49 1 507.2 1-50 -y 369.0 N
.--- ===1 N
CO
I

-I
D
D.,f_D
(D.,N,, 0,...y..N=
HNA..,,..),..Br HN''"'-"Br --,.7 395.1, -----)-"N 437.1, i 1-81 ,) 397.1 439.1 ..TN,i .) ) LIO N
I

ID.,, NIN 283.0 0 N
HN,',.,. i,Br , =-- -i=
1-100 1-101 HN'Br 297.0, 285.0 299.0 6 ,i4t N N
/
I I
0....,N.., 0.....N.,..
,.. I 281.0, 281.0, 1-102 HN-Br 1-103 HN"'-'-'"'Br C
283.0 --"N 283.0 I''N
) N
I
0.....N,.. I
0.õ141,,, ilIkr HN3...j.Br 'Br 295.0, 283.0, -----js"N 297.0 285.0 II
cl-/N-N

0.,. -.IN ======= 1.
IINAjL,Br 284.0, HeBr 298.0, 286.0 .--)'N
300.0 N
b / ...,,T) F
I I
0*.N.,1 OyN,1 1.,Br FIN)*Br I 448.1, 1 435.1, 450.1 437.1 v.-' .$) ) N N
6 e oyNI 0 jN
HN''Br HN Br =y =' 13 1-1 1. ,--N
448.1, 417.1, 1-112 - . . y 450.1 419.1 .....\(N) @) ) N N

,1N O)a HN'N....A.Br HN Br N 382.1, ,),) 403.1, N--) 384.1 405.1 TJ

ONI
''.
k _.,,_1 I
HN- --'''''--- -Br ,, 1 HNBr -'1 1 446.1, EN 396.1, 1-117 1-118 \ N, ,......,N 448.1 Rsj 398.1 (¨k ) N
N

\

0., ,N
=-=,---'-= ,.., 1 ,... I Hisr-------"Br HINI-Br ik.srq 396.1, 1-119 394.1, .........:Ls'N 1-120 N
µ tµi 396.1 398.1 ti NJ
N
d 0 1RS) \
I
CNõN.,1 HN)k...,.iLBr I
0,-õ,.....õNõ
380.0, HN.--...'N-Br 294.0, 1-122 psi N 382.0 ---"4"N 296.0 d 0 ti NI
-, i 1 (NA HN Br HNJ.,...A.Br 310.0, ..-.1.7 391.0, --tii 312.0 393.0 N

0., ,,IN 0*. .N
1-iN)kNJI,Br HNAõ.J.Br 327.0, 325.0, 329.0 EN 327.0 / 0 \ 0--) I
0.,.. .,N 1 1 ON
HNA.,-Br HN
366.1, 352.0, t'll 368.0 1-135 E N
...N.) 354.0 ,I
A
Y
0., 1 0.,,..N., (3. õIN I
HN....õ11,Br 311.0, FiN"--C-s''= Br ts 313.0 1-138 t 378.1..N
-- il N 380.1 'N, N
N --) 0õ, d 0.,,,,,,, N,õ 1 I Cliel HN'' -'-''s=-'.*Br HNA.,,,I-(.Br 364.0, 297.0, 366.0 1-139 EN 364.0, e( 299.0 <( cN-N

*N,i ====- ',..
HN HN Br Br 311.0, 311.0, (-1= 313.0 313.0 N¨N
---- $N¨N

0,N,.1 0 N
FINj%,11. Br HN 's=-,..,, '..N.-').'Br .0, 379.0, eLii 1-147 -''''N
N-N 329.0 ., ..1.) 381.0 \
c I
0. N.

I HN '''Br 0õ.11s1 )%...)(Br 367.0, ...il 448.1, 1 369.0 450.1 e)(1' N

I
I0=k,=,"NN=
EIN`-..;.)..Br HNI Br .,L.
NV N
1-150 N*(N 380.0, 1-151 y 435.1, y382.0 437.1 ) N

I I
0 N 0,N, s-N-- N
HN"N-ss---"-N*Br HN CI
420.7, 1-152 --. N 1-153 405.1 422.7 e) ,;.......
N N

r 1 .
0.., .,IN 0''=:,'NN-HNAO,.Br õ_ I
1-IN"."--'Br =='. y =-').-N
1 448.1, 449.1, 450.1 4 N 451.1 õ.
t) ) N N

I I
0.,., ,1N 0 N
===== ====
HN),...)-1-.Br fiN""Br =====7 ====== .fil 1 436.1, i 450.1, 438.1 452.1 N N
IN) Ll 0.,... 0, r N, ...IN I
FINA.,...,i..Br 0 N
=-=" ====
.., I
HN---'"------'s Br .71 462.1, ..---i--380.2, 1-158 i 1-159 ---464.1 -.)., N
382.2 4õ,..N
1)(R) N ) 0 .

0N'-=

Hte."." Br --<.=," `-,_ I
N HN N Br 11 435.1, 393.8, 1-160 -. N 1-161 -)- ' "N
437.1 395.8 6 L...,, I I
0......N. 0 N
=== -, HNBr FIN3r -.. y 1-163 ..,-i 450.1, 1-164 1, 450.1, 452.1 ) 452.1 . ) ......Nj N N
)7) L.) 0.õ 0., I

'-'-`=,-- -HN'Br 424.1, Li,si 426.1 N
N-' floc' _ Intermediate 1-4 WO :00 2r..1/16i113.. 504 (3-(acetoxymethyl)-2-(7,7-dimethy1-1-oxo-1,6,7,8-tetrahydro-21/-cyclopenta[4,51pyrrolo[1,2-alpyrazin-2-y1)pyridin-4-y1)boracic acid I
...- Step 1 0Hr... \ i 1 ...,-, Step 2 /
-6ArN c Step 3 OH fy i N \
Ci,, s, Nylz--.= HO..131 -,.. N ----Step 1: 2-(4-chloro-3-(hydroxymethyl)pyridin-2-y1)-7,7-dimethy1-7,8-dihydro-2H-cyclopenta[4,51pyrrolo[1,2-alpyrazin-1(611)-one At 0-5 C, under nitrogen, to a solution of 4-chloro-2-(7,7-dimethyl-1-oxo-1,6,7,8-tetrahydro-211-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-y1) nicotinaldehyde (1.71 g, 5.0 mmol) (intermediate 1-55) in methanol (5 mL) and dichloromethane (15 mL) was added sodium borohydride (0.13 g, 3.5 mmol), and the mixture was reacted at this temperature for 10 minutes.
A saturated aqueous ammonium chloride solution (5 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (30 mL x 2). The organic phase was collected and combined, and concentrated in vacuum under reduced pressure to give the target product (1.72 g, yield 100%), which was directly used in the next step. [M+Hr 344.1 Step 2: Acetic acid (4-chloro-2-(7,7-dimethy1-1-oxo-1,6,7,8-tetrahydro-2H-cyclopenta[4,51pyrrolo[1,2-alpyrazin-2-y1)pyridin-3-y1)methyl ester At 0-5 C, under nitrogen, to a solution of 2-(4-chloro-3-(hydroxymethyppyridin-2-y1)-7,7-dimethy1-7,8-dihydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one (1.72 g, 5.0 mmol) and triethylamine (2.53 g, 25 mmol) in dichloromethane (30 mL) was added acetylchloride (1.18 g, 15 mmol), and the mixture was reacted at this temperature for 1 hour. Water (20 mL) and dichloromethane (30 mL) were added to the reaction solution, the organic phase was collected and combined, and concentrated in vacuum under reduced pressure, and the resulting residue was purified with silica gel column chromatography (petroleum ether/ethyl acetate) to give the target product (1.65 g, yield 86%). [M+Hr 386.1 Step 3: (3-(acetoxymethyl)-2-(7,7-dimethy1-1-oxo-1,6,7,8-tetrahydro-2H-cyclopental4,51pyrrolo11,2-a)pyrazin-2-yl)pyridin-4-y1)boracic acid Under nitrogen, to a solution of acetic acid (4-chloro-2-(7,7-dimethyl-1-oxo-1,6,7,8-tetrahydro-211-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)pyridin-3-yOmethyl ester (3.0 g, 7.79 mmol), bis(pinacolato)diboron (5.9 g, 23.3 mmol) in 1,4-dioxane (120 mL) was added Xphos (333 mg, 0.7 mmol), Pd(dppf)C12 CH2C12 (570 mg, 0.7 mmol) and potassium acetate (2.3 g, 23.3 mmol). The mixture was reacted at 90 C for 16 hours, and then cooled to room temperature. The reaction solution was concentrated in vacuum under reduced pressure, and the resulting residue was purified with silica gel column chromatography (methanol/water) to give the target product (2.9 g, yield 94%). [M+H] 396.1 The intermediates in the following table were prepared with corresponding materials and reagents according to the preparation steps of intermediate 1-4:

LC-MS
Intermediate Structural formula IM+Hr ?H

7. 1 HO- Bs-TY1 OH -'- 1VILN
1-121 411.1 HO -OH .N
1-129 368.1 HO' Bi Intermediate 1-5 5-bromo-3((1-ethy1-11/-1,2,3-triazole-4-y1)amino)-1-methylpyrazin-2(1H)-one N
NH2 oI
()NN _________________ /, =
N¨N
N
N¨N

Under nitrogen, 3,5-dibromo-1-methylpyrazin-2(1H)-one (5.0 g, 18.7 mmol) and 1-ethyl-1H-1,2,3-triazole-4-amine (2.1 g, 18.7 mmol) were dissolved in /sl-methylpyrrolidone (7 mL).
The mixture was reacted at 120 C for 3 hours, and cooled to room temperature.
The mixture was filtered, and the filter cake was washed with methanol (5 mL), to give the target product (3.9 g, yield 50%). [M+H] 299.0, 301.0 The intermediate in the following table was prepared with corresponding materials and reagents according to the preparation steps of intermediate 1-5:
LC-MS
Intermediate Structural formula 11M+Hr HN
1-6 L 313.0, 315.0 eN
N-N
Intermediate 1-13 (S)-5-bromo-1,6-dimethy1-34(5-(2-methyl-4-(oxetan-3-yOpiperazin-1-y1)pyridin-2-yl)amino)pyridin-2(1H)-one HN Br 9 Step 1 BrilL NH Step 2 Br., kw. Step 3 11õ:1;Nilsi Br Br Step 1: 3,5-dibromo-6-methylpyridin-2(1H)-one Under nitrogen, to a solution of 6-methylpyridin-2(1H)-one (949 mg, 8.7 mmol) in DMF(30 mL) was added NBS (3.1 g, 17.4 mmol). The mixture was reacted at room temperature for 4 hours. The reaction solution was poured into water (50 mL), and the precipitated solid was collected, and then washed with methanol to give the target product, which was directly used in the next step.
Step 2: 3,5-dibromo-1,6-dimethylpyridin-2(1H)-one Under nitrogen, to a solution of 3,5-dibromo-6-methylpyridin-2(1H)-one (2.3 g, 8.7 mmol) in DMF(30 mL) was added iodomethane (1.3 g, 8.7 mmol) and cesium carbonate (1.6 g, 11.3 mmol). The mixture was reacted at room temperature for 2 hours. The reaction solution was poured into water (50 mL), the precipitated solid was collected, and then the solid was washed with methanol to give the target product (2.2 g, two-step yield 92%). [M+H]
281.8 Step 3: (S)-5-bromo-1,6-dimethy1-34(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)pyridin-2(1H)-one The intermediate 1-13 was prepared with 3,5-dibromo-1,6-dimethylpyridin-2(1H)-one and corresponding reagents according to the corresponding steps of intermediate 1-2. [M+H] 448.1, 450.1 Intermediate 1-16 (S)-6-chloro-2-ethy1-44(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino) pyridazine-3(211)-one jN01 0 N.N Step 10 4 Step 2 -11" µIs1 -311"
Br CI
'-'-L, Step 1: 4-bromo-6-chloro-2-ethy1pyridazine-3(21)-one At 0-5 C, under nitrogen, to a solution of 4-bromo-6-chloro-3(2H)-one (1.0 g, 4.8 mmol) in DMF(20 mL) was added 60% sodium hydride (mineral oil dispersion) (0.46 g, 11.5 mmol). The mixture was reacted at 0-5 C for 30 minutes, then iodoethene (1.5 g, 9.6 mmol) was added, and the reaction was continued at room temperature for 5 minutes. The reaction solution was poured into water, extracted with ethyl acetate, the organic phase was collected and combined, and concentrated in vacuum under reduced pressure, and the resulting residue was purified with silica gel column chromatography (methanol/water) to give the target product (0.91 g, yield 80%). [M+H] 238.9 Step 2: (S)-6-chloro-2-ethy1-4-05-(2-methyl-4-(oxetan-3-yl)piperazin-l-yl)pyridin-2-yl)amino) pyridazine-3(2H)-one The intermediate 1-16 was prepared with 4-bromo-6-chloro-2-ethylpyridazine-3(211)-one and corresponding reagents according to the corresponding steps of intermediate 1-2. [M+H]
405.1 Intermediate 1-31 5-bromo-1-methy1-34(1-(2,2,2-trifluoroethyl)-1H-1,2,3-triazole-4-yl)amino)pyridin-2(1 H)-one 0õ !kJ, i1:s2 Step I el-õN Step 2 Mr. 'Br el\-14 NN ek H isi = = N-S\--F 14 F F
2r-F
F F

Step 1: 4-nitro-1-(2,2,24rifluoroethy1)4H4,2,3-triazo1e At 0-5 C, under nitrogen, to a solution of 4-nitro-1H-1,2,3-triazole (4.0 g, 35.1 mmol), 2-trifluoroethanol (5.12 mL, 43.8 mmol) and triphenylphosphine (18.4 g,43.8 mmol) in tetrahydrofuran (180m1) was added DIAD (13.9 g, 43.8 mmol). The mixture was reacted at 60 C
for 16 hours, and then cooled to room temperature, concentrated in vacuum under reduced pressure, and the resulting residue was purified with silica gel column chromatography (petroleum ether/ethyl acetate) to give the target product (4.61 g, yield 68%). [M+H] 197.0 Step 2: 5-bromo-1-methyl-34(1-(2,2,2-trilluoroethyl)-1 H - 1,2,3-triazole-4-yl)amino)pyridin-2(11P-one The intermediate 1-31 was prepared with 4-nitro-1-(2,2,2-trifluoroethyl)-1/1-1,2,3-triazole and corresponding reagents according to the corresponding steps of intermediate 1-3. [M+H]
352.0, 353.9 The intermediates in the following table were prepared with corresponding materials and reagents according to the preparation steps of intermediates 1-31, 1-3 and 1-5:
Structural LC-MS Structural LC-MS
Intermediate Intermediate formula [M+111+ formula 1M+Il1OALN
L
HN- 'Br L l."
316.0, 317.0, e r 1-32 -N 318.0 1-33 N 319.0 N-N N-N

1,N 0 N
HNA,),õBrHNNBr 353.0, 343.0, e 1-34 LN 1-42 (-)'N
354.9 345.0 Sµ-F0 F F
Intermediate 1-37 5-bromo-1-methy1-34(1'-(oxetan-3-y1)-1',2',3',6'-tetrahydro-1[3,4'-bispyridini-y1)amino)pyridin-2(1H)-one 0,, .N

fitsr 'Br LN
0,13:
Step 1 Step 2 r.;;
0.=
'LN:A1 Boc Bot 'N

Step 1: t-buvl 6-nitro-3',6'-dihydro-I3,4'-bispyridini-1'(2'H)carboxylate Under nitrogen, to a solution of 1-nitrogen-tert-buty1-4,5-cyclohexene-4-borate (4.41 g, 15 mmol), 5-fluoro-2-nitropyridine (3.03 g, 15 mmol) in 1,4-dioxane (20 mL) and water (2 mL) was added Pd(dppf)C12 CH2C12 (612 mg, 0.75 mmol) and sodium carbonate (3.18 g, 30 mmol). The mixture was reacted at 100 C for 3 hours, and then cooled to room temperature, concentrated in vacuum under reduced pressure, and the resulting residue was purified with silica gel column chromatography (petroleum ether/ethyl acetate) to give the target product (4.58 g, yield 100%).
[M+Hr 306.1 Step 2: 5-bro mo- I -methyl-34(1 '-(oxetan-3-yI)-1 yl)amino)py rid in-2(1H)-one The intermediate 1-37 was prepared with t-butyl 6-nitro-3',6'-dihydro-[3,4'-bispyridin ]-1'(2'H) carboxylate and corresponding reagents according to the corresponding steps of intermediate 1-2. [M+1-1]+ 417.0, 419.0 The intermediate in the following table was prepared with corresponding materials and reagents according to the preparation steps of intermediate 1-37:
LC-MS
Intermediate Structural formula [M+11]

1-IN)0.13r N
1-38 412.0,414.0 Intermediate 1-43 (S)-5-bromo-1-methy1-34(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyrazin-2-yl)amino)pyridin-2(1H)-one rkN Step 1 Nyli Step 2 N
Ny) Br =Cs) ) 60c Step 1: t-butyl (S)-3-methyl-4-(5-nitropyrazin-2-yl)piperazin-1-carboxylate To a solution of 2-bromo-5-nitropyrazine (1.22 g, 6.0 mmol), t-butyl (S)-3-methylpiperazin-1-carboxylate (1.00 g, 5.0 mmol) in DMF(10 mL) was added potassium carbonate (1.38 g, 10 mmol). The mixture was reacted at 80 C for 4 hours, and then cooled to room temperature, concentrated in vacuum under reduced pressure, and the resulting residue was purified with silica gel column chromatography (petroleum ether/ethyl acetate) to give the target product (1.50 g, yield 93%). [M+H-56]+ 268.1 Step 2: (S)-5-bromo-l-methy1-3-((5-(2-methyl-4-(oxetan-3-y1)piperazin-l-y1)pyrazin-2-y1)amino)pyridin-2(1H)-one The intermediate 1-43 was prepared with t-butyl (S)-3-methyl-4-(5-nitropyrazin-2-y1) piperazin-l-carboxylate and corresponding reagents according to the corresponding steps of intermediate 1-2. [M+H] 435.1, 437.1 Intermediate 1-44 (S)-5-bromo-1-methy1-3-((5-(2-methyl-4-(oxetan-3-y1)piperazin-1-y1)pyrimidin-2-y1)amino)pyridin-2(1H)-one PMEI.N-PMB
PMB,N,PMB
NEh N
1,1:--"LN Step 1 Step 2 : Step 3 N
Br Br i(s) Boo IINAA.Br NV" N N'=" N
Step 4 y Step 5 N
irs) I
µ1=1"
Bac Step 1: 5-bromo-N,N-bis(4-methoxy benzyl)pyrimidin-2-amine At 0-5 C, under nitrogen, to a solution of 5-bromopyrimidin-2-amine (3.48 g, 20 mmol) in tetrahydroffiran (60 mL) was added 60% sodium hydride (mineral oil dispersion) (1.72 g, 43 mmol). The mixture was reacted at 0-5 C for 30 minutes, then p-methoxybenzyl chloride (7.83 g, 50 mmol) was added, and the reaction was continued at 75 C for 8 hours. The reaction solution was poured into water, extracted with ethyl acetate, the organic phase was collected and combined, and concentrated in vacuum under reduced pressure, and the resulting residue was purified with silica gel column chromatography (petroleum ether/ethyl acetate) to give the target product (2.07 g, yield 25%). [M+Hr 414.1, 416.1 Step 2: 1-busy! (S)-4-(2-(bis(4-methoxy benzAamino)pyrimidin-5-y1)-3-methylpiperazin-1-carboxylate Under nitrogen, to a solution of 5-bromo-N,N-bis(4-methoxy benzyl)pyrimidin-2-amine (2.07 g, 5.0 mmol) and 1-butyl (S)-3-methylpiperazin-l-carboxylate (10.0 g, 49.0 mmol) in toluene (30 mL) was added BINAP (311 mg, 0.50 mmol), Pd2(dba)3 (229 mg, 0.25 mmol) and tert-butoxysodium (960 mg, 10 nuriol). The mixture was reacted at 80 C for 8 hours, and then cooled to room temperature. The reaction solution was concentrated in vacuum under reduced pressure, and the resulting residue was purified with silica gel column chromatography (petroleum ether/ethyl acetate) to give the target product (1.60 g, yield 30%). [M+H] 534.3 Step 3: (S)-5-(2-methylpiperazin-1-yl)pyrimidin-2-amine Under nitrogen, a solution of t-butyl (S)-4-(2-(bis(4-methoxy benzypamino)pyrimidin-5-y1)-3-methylpiperazin-1-carboxylate (1.60 g, 3.0 mmol) in trifluoroacetic acid (1() mL) was stirred at room temperature for 30 minutes, concentrated in vacuum under reduced pressure, to give the target product, which was directly used in the next step. [M+H] 194.1 Step 4:1-busy! (S)-4-(2-aminopyrimidin-5-yI)-3-methylpiperazin-l-carboxylate To a solution of (S)-5-(2-methylpiperazin-1-yl)pyrimidin-2-amine obtained from the previous step and di-tert-butyl dicarbonate (720 mg, 3.3 mmol) in dichloromethane (10 mL) was added triethylamine (455 mg, 4.5 mmol). The mixture was reacted at room temperature for 1 hours. The mixture was concentrated in vacuum under reduced pressure, and the resulting residue was purified with silica gel column chromatography (dichloromethane/methanol) to give the target product (880 mg, two-step yield 100%). [M+H] 294.1 Step 5: (S)-5-bromo-1-methy1-34(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yppyrimidin-2-yl)amino)pyridin-2(111)-one The intermediate 1-44 was prepared with t-butyl (S)-4-(2-aminopyrimidin-5-y1)-methylpiperazin-1-carboxylate and corresponding reagents according to the corresponding steps of intermediate 1-2. [M+H] 435.0, 437.0 Intermediate 1-45 5-b ro ethy1-34(5-((tetrahyd ro-211-pyran-3-yl)amino)pyridi n-2-yl)ami no)pyridin-2(111)-one NO2 .===
Step 1 r 14N -" Br Stec) 2 N
HN

Step 1: 6-nitro-N-(tetrahydro-2H-pyran-3-yl)pyridin-3-amine Under nitrogen, to a solution of tetrahydro-2H-pyran-3-amine (0.61 g, 6.0 mmol) and 5-bromo-2-nitropyridine (1.46 g, 7.2 mmol) in 1,4-dioxane (50 mL) was added BINAP (0.37 g, 0.60 mmol), Pd2(dba)3 (0.55 g, 0.60 mmol) and cesium carbonate (3.91 g, 12 mmol). The mixture was reacted at 100 C for 16 hours, and then cooled to room temperature. The reaction solution was concentrated in vacuum under reduced pressure, and the resulting residue was purified with silica gel column chromatography (dichloromethane/methanol) to give the target product (0.72 g, yield 54%). [M+H] 224.1 Step 2: 5-bromo-1-methy1-3-05-((tetrahydro-2H-pyran-3-yl)amino)pyridin-2-y1)amino)pyridin-2(111)-one The intermediate 1-45 was prepared with 6-nitro-N-( tetrahydro-2H-pyran-3-y1) pytidin-3-amine and corresponding reagents according to the corresponding steps of intermediate 1-3.
[M+Hr 379.0, 381.0 The intermediate in the following table was prepared with corresponding materials and reagents according to the preparation steps of intermediate 1-45:
LC-MS
Intermediate Structural formula IIVI+11]+
O N
I
==-=:1µ' 409.0,411.0 No (R) OH

Intermediate 1-47 5-bromo-1-methy1-34(5-(morpholin-4-carbonyl)pyridin-2-yl)amino)pyridin-2(111)-one h.1112 )="µ Alf-12 HN 'Sr Step 1 L.' fl Step 2 0 W.-N.1 "OH L0 Step 1: (6-aminopyridin-3-yI)(morpholino)ketone Under nitrogen, a solution of 6-aminonicotinic acid (1.38 g, 10 mmol), CDI(1.95 g, 12 mmol) in DMF (12 mL) was reacted at 70 C for 1 hour, and then stirred at room temperature for 1 hour. Morpholine (1.74 g, 20 mmol) was added to the mixture, and the mixture was reacted at room temperature for 16 hours. The reaction solution was concentrated in vacuum under reduced pressure, and the resulting residue was purified with silica gel column chromatography (dichloromethane/methanol) to give the target product (1.05 g, yield 51%).
[M+H] 208.1 Step 2: 5-bromo-1-methy1-34(5-(morpholin-4-carbonyl)pyridin-2-yl)amino)pyridin-2(1 H)-one The intermediate 1-47 was prepared with (6-arninopyridin-3-y1)(morpholino)ketone and corresponding reagents according to the corresponding steps of intermediate 1-3. [M+H] 393.0, 395.0 The intermediates in the following table were prepared with corresponding materials and reagents according to the preparation steps of intermediate 1-47:
IC-MS
Intermediate Structural formula [M+Hr I
HN
1-48 N 406.0,408.0 ON

HNBr 1-165 396.0, 398.0 Nj1r.

Intermediate 1-52 4-chloro-2-(6-fluoro-l-oxopyrazino(1.2-al indoI-2(1H)-yl)nicotinaldehyde F.
Step F rLo) Step 2 b F\
r¨

Step 3 -)pb.
CIkI, '1 'r Step 1: Ethyl 1-(2,2-diethoxyethyl)-7-fluoro-1H-indo1-2-carboxylate To a solution of ethyl 7-fluoro-1H-indo1-2-carboxylate (2.07 g, 10 mmol) in DMF(15 mL) was added 2-bromo-1,1-diethoxyethane (4.0 g, 20 mmol) and cesium carbonate (8.2 g, 25 mmol).
The mixture was reacted at 110 C for 16 hours, and then cooled to room temperature, poured into water, and extracted with ethyl acetate. The organic phase was collected and combined, and concentrated in vacuum under reduced pressure, and the resulting residue was purified with silica gel column chromatography (petroleum ether/ethyl acetate) to give the target product (2.5 g, yield 77%). [M+H-Et0Hr 278.1 Step 2: 6-fluoropyrazino[1,2-af indo1-1(210-one To a solution of ethyl 1-(2,2-diethoxyethyl)-7-fluoro-1H-indo1-2-carboxylate (2.5 g, 7.7 mmol) in acetic acid (50 mL) was added ammonium acetate (12 g, 154 mmol). The mixture was reacted at 110 C for 16 hours, and then cooled to room temperature, concentrated in vacuum under reduced pressure, and the resulting residue was purified with silica gel column chromatography (petroleum ether/ethyl acetate) to give the target product (2.5 g, yield 77%1).
[M+Hr 203.0 Step 3: 4-chloro-2-(6-fluoro-1 -oxopyrazino[1,2-alindo1-2(1H)-yl)nicotinaldehyde The intermediate 1-52 was prepared with 6-fluoropyrazino[1,2-a] indo1-1(2H)-one and corresponding reagents according to the corresponding steps of intermediate I-1. [M+H] 342.0 The intermediates in the following table were prepared with corresponding materials and reagents according to the preparation steps of intermediates 1-52 and I-1:
LC-MS
Intermediate Structural formula IM+Hr 1-53 F 342.0 I

N
1-59 342.0 1-66 32.5.0 I

1-70 324.0 I

1-71 ,N 342.0 Intermediate 1-58 4-chloro-2-(7,7-difluoro-1-oxo-6,7,8,9-tetrahydropyrazino[1,2-alindo1-2(1H)-yl)nicotinaldehyde F, it 1.1 0 Step 1 Ii3,1-\ Ste , p 2 rçJN \
"
HN.

Step 3 Step 4 ) 0 ,µõN

Step 1: 7,7-difluoro-8,9-dihydropyrazino[1,2-ajindol-1,6(2H,7H)-dione The target compound was prepared with ethyl 6,6-fluoro-7-oxo-4,5,6,7-tetrahydro-1H-indo1-2-carboxylate according to the corresponding steps of intermediate I-1.
[M+Hr 239.0 Step 2: 7,7-difluoro-6-hydroxyl-6,7,8,9-tetrahydropyrazino[1,2-alindol-1(211)-one At 0-5 C, under nitrogen, to a solution of 7,7-difluoro-8,9-dihydropyrazino[1,2-c]indol-1,6(2H,7H)-dione (500 mg, 2.1 mmol) in methanol (10 mL) was added sodium borohydride (239 mg, 6.3 mmol), and the mixture was reacted at this temperature for 10 minutes.
A saturated aqueous ammonium chloride solution (5 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (10 mL x 2). The organic phase was collected and combined, and concentrated in vacuum under reduced pressure to give the target product, which was directly used in the next step.
Step 3: 7,7-difluoro-6,7,8,9-tetrahydropyrazino[1,2-alindol-1(211)-one Under nitrogen, to a solution of 7,7-difluoro-6-hydroxy1-6,7,8,9-tetrahydropyrazino[1,2-a]indo1-1(210-one obtained from the previous step in trifluoroacetic acid (5 mL) was added triethylsilane (771 mg, 6.3 mmol). The mixture was reacted at room temperature for 1 hour, and concentrated in vacuum under reduced pressure, a saturated aqueous sodium bicarbonate solution (10 mL) was added to the resulting residue, and the mixture was extracted with dichloromethane (10 mL x 2). The organic phase was collected and combined, and concentrated in vacuum under reduced pressure, and the resulting residue was purified with silica gel column chromatography (methanol/water) to give the target product (120 mg, two-step yield 26%).
[M+H] 225.0 Step 4: 4-chloro-2-(7,7-difluoro-1-oxo-6,7,8,9-tetrahydropyrazinol1,2-a)indol-2(1H)-yl)nicotinaldehyde The intermediate 1-58 was prepared with 7,7-difluoro-6,7,8,9-tetrahydropyrazino[1,2-c]indol-1(210-one and corresponding reagents according to the corresponding steps of intermediate I-1. [M+H] 364.0 The intermediate in the following table was prepared with corresponding materials and reagents according to the preparation steps of intermediate I-58:
LC-MS
Intermediate Structural formula IM+III+
F
1-60CI,N 364.0 I
Intermediate 1-61 4-chloro-2-(8,I0-difluoro-l-oxopyrazinoll,2-aiindol-2(1H)-y1)nicotinaldehyde Step 1 FT-s_sx.. 0 Step 2 Step 1: Ethyl 3,5-difluoro-1H-indo1-2-carboxylate At 0-5 C, under nitrogen, to a solution of ethyl 5-fluoro-1H-indo1-2-carboxylate (4.14 g, 20 mmol) in acetonitrile (100 mL) was added Selectfluor (7.08 g, 20 mmol), and the mixture was reacted at this temperature for 16 hours. A saturated aqueous ammonium chloride solution (20 mL) and water (100 mL) were added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL x 2). The organic phase was collected and combined, and concentrated in vacuum under reduced pressure, and the resulting residue was purified with silica gel column chromatography (ethyl acetate/petroleum ether) to give the target product (2.4 g, yield 53%).
[M+H] 226Ø
Step 2: 4-chloro-2-(8,10-difluoro-1-oxopyrazino[1,2-alindo1-2(1H)-yl)nicotinaldehyde The intermediate 1-61 was prepared with ethyl 3,5-difluoro-1H-indo1-2-carboxylate and corresponding reagents according to the corresponding steps of intermediate 1-52. [M+Hr 360.0 Intermediate 1-62 Acetic acid (2-(9-bromo-7,7-dimethy1-1-oxo-1,6,7,8-tetrahydro-211-cyclopenta[4,51pyrrolo[1,2-alpyrazin-2-y1)-4-chloropyridin-3-yOmethyl ester .N
I I
0 Br At 0 C, to a solution of acetic acid (4-chloro-2-(7,7-dimethy1-1-oxo-1,6,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)pyridin-3-yOmethyl ester (800 mg, 2.07 mmol) in dichloromethane (30 mL) was added NBS (367 mg, 2.07mm01). The mixture was reacted at room temperature for 16 hours, quenched with a saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic phase was collected and combined, dried with anhydrous sodium sulfate, and concentrated in vacuum under reduced pressure, and the resulting residue was purified with silica gel column chromatography (petroleum ether/ethyl acetate) to give the target product (800 mg, yield 83%). [M+H] 464.0,466.0 Intermediate 1-63 4-chloro-2-(7,7-dimethy1-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[4,51pyrrolo[2,1-/I 11,2,41triazin-3-yl)nicotinaldehyde Step 1 \ Step 2 - O===\ N

Step Step 1: Ethyl 1-amino-5,5-dimethy1-1,4,5,6-tetrahydrocyclopentadieno[b]pyrrole-carboxylate At 0-5 C, under nitrogen, to a solution of ethyl 5,5-dimethy1-1,4,5,6-tetrahydrocyclopentadieno[b]pyrrole-2-carboxylate (5.0 g, 24.1 mmol) in DMF(30 mL) was added 60% sodium hydride (mineral oil dispersion) (1.06 g, 26.5 mmol). The mixture was reacted at 0-5 C for 30 minutes, then 0-(2,4-dinitrophenyl) hydroxylamine (5.3 g, 26.5 mmol) was added to the reaction solution, and the mixture was reacted at room temperature for 3 hours.
The mixture was concentrated in vacuum under reduced pressure, and the resulting residue was purified with silica gel column chromatography (petroleum ether/ethyl acetate) to give the target product (4.3g, yield 75%). [M+Hr 223.0 Step 2: 7,7-dimethy1-7,8-dihydro-3H-cyclopenta[4,51pyrrolo[2,1-f111,2,41triazin-4(6H)-one Under nitrogen, to a mixture of ethyl 1-amino-5,5-dimethy1-1,4,5,6-tetrahydrocyclopentadieno[b]pyrrole-2-carboxylate (4.3g, 19.3 mmol) and formamide (30 mL) was added ammonium acetate (7.4 g, 96.5 mmol). The mixture was reacted at 140 C for 16 hours, and then cooled to room temperature. The mixture was filtered, and the filter cake was collected and washed with methanol to give the target product (3.1 g, yield 80%). [M+H]
204.0 Step 3: 4-chloro-2-(7,7-dimethy1-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[4,51pyrrolo[2,1-f][1,2,4]triazin-3-y1)nicotinaldehyde The intermediate 1-63 was prepared with 7,7-dimethy1-7,8-dihydro-311-cyclopenta [4,5]
pyrrolo [2,1-f][1,2,4] triazin-4(610-one and corresponding reagents according to the corresponding steps of intermediate I-1. [M+H] 343.1 The intermediates in the following table were prepared with corresponding materials and reagents according to the preparation steps of intermediate 1-63:
LC-MS
Intermediate Structural formula EM-F11]
O
rõN.N
1-93 329.0 I

O
1-97 CINyJ7 347.0 I
o F
Intermediate 1-68 (8-((tert-butoxycarbonyl) (1-ethy1-1H-1,2,3-triazole-4-Aamino)-(1,2,41triazolo11,5-a] pyridin-6-yl)boracic acid N N N .

HN' Soc Step 1 N C Bac I Step 2 N õ.014 ek N /.)==
OH

( The intermediate 1-68 was prepared with intermediate 1-21 and corresponding reagents according to step 1 of intermediate 1-74 and step 6 of intermediate 1-2. [M+1-1] 374.1 The intermediate in the following table was prepared with corresponding materials and reagents according to the preparation steps of intermediate 1-68:
LC-MS
Intermediate Structural formula [M+Hr Bocs-NA..õõis, OH

1-72 501.2 Intermediate 1-74 4-chloro-2-(7-methy1-1-oxo-6,7,8,9-tetrahydropyrazino[1,2-alindol-2(1 H)-yl)nicotinaldehyde os) Step 1 Bocsr,:p Step 2 HN HN"
0?

4s) Step 3 Step 4 rf.,0 CI )..y.N

0 N , Step I: 7-oxo-4,5,6,7-tetrahydro-1H-indo1-1,2-dicarboxylic acid 1-(tert-butyl)ester 2-ethyl ester To a solution of ethyl 7-oxo-4,5,6,7-tetrahydro-1H-indo1-2-carboxylate (2.07 g, 10 mmol) and di-tert-butyl dicarbonate (7.51 g, 30 mmol) in tetrahydrofiiran (30 mL) was added 4-dimethylaminopyridine (0.12 g, 1.0 mmol). The mixture was reacted at room temperature for 16 hours. The mixture was concentrated in vacuum under reduced pressure, and the resulting residue was purified with silica gel column chromatography (petroleum ether/ethyl acetate) to give the target product (3.07 g, yield 1004). [M+Na] 330.3 Step 2: Ethyl 6-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indo1-2-carboxylate Al -78 C, under nitrogen, to a solution of 7-oxo-4,5,6,7-tetrahydro-1H-indo1-1,2-dicarboxylic acid 1-(tert-butyl)ester 2-ethyl ester (3.07 g, 10 mmol) in tetrahydrofuran (50 mL) was dropwise added 1M HMDSLi/tetrahydrofuran solution (24 mL, 24 mmol), the mixture was naturally warmed to 0 C, and the reaction was continued for 30 minutes. At -78 C, iodomethane (3.41 g, 24 mmol) was dropwise added to the reaction solution, the mixture was naturally warmed to room temperature, and the reaction was continued for 4 hours. The reaction solution was cooled to 0 C, and quenched by adding a saturated aqueous ammonium chloride solution, extracted with ethyl acetate (50 mL x 2). The organic phase was collected and combined, dried with anhydrous sodium sulfate, and concentrated in vacuum under reduced pressure. Under nitrogen, the resulting residue trifluoroacetic acid (10 mL) solution was stirred at room temperature for 30 minutes, and concentrated in vacuum under reduced pressure, and the resulting residue was purified with silica gel column chromatography (water/methanol) to give the target product (1.19 g, yield 54%). [M+H] 221.1 Step 3: Ethyl 6-methyl-4,5,6,7-tetrahydro-1H-indo1-2-carboxylate Under nitrogen, to a solution of ethyl 6-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indo1-2-carboxylate (1.19 g, 5.38 mmol) in trifluoroacetic acid (10 mL) was added triethylsilane (2.5 m L). The mixture was reacted at room temperature for 16 hours, and concentrated in vacuum under reduced pressure, and the resulting residue was purified with silica gel column chromatography (methanol/water) to give the target product (980 mg, yield 88%). [M+H] 208.1 Step 4: 4-chloro-2-(7-methyl-l-oxo-6,7,8,9-tetrahydropyrazino(1,2-alindol-2(1H)-yl)nicotinaldehyde The intermediate 1-74 was prepared with ethyl 6-methy1-4,5,6,7-tetrahydro-IH-indol-2-carboxylate and corresponding reagents according to the corresponding steps of intermediate I-I.
[M+H] 342.0 Intermediate 1-75 4-chloro-2-(7,7-dimethyl-l-oxo-1,6,7,8-tetrahydro-2 H-cyclopenta14,51pyrrololl,2-di 11,2,41triazin-2-yl)nicotinaldehyde H-çJ Step 1 H Step 2H2N Ne"N I
HN
:;

yf Step 3 I CI N
1.75 y Step 1: 5,5-dimethy1-1,4,5,6-tetrahydrocyclopentadienothipyrrole-2-carbohydrazide A solution of ethyl 5,5-dimethy1-1,4,5,6-tetrahydrocyclopentadieno[b]pyrrole-2-carboxylate (2.49 g, 12 mmol), an aqueous hydrazine hydrate solution (20 mL, 36 mmol) in ethanol (8 mL) was reacted in microwave reactor at 150 C for 2 hours, and then cooled to room temperature. The reaction was filtered and washed with water, and the filter cake was collected, and dried in vacuum under reduced pressure to give the target product (2.09 g, yield 90%).
[M+H] 194.1 Step 2: 7,7-dimethy1-7,8-dihydro-2H-cyclopenta[4,51pyrrolo[1,2-d][1,2,41triazin-1(611)-one Under nitrogen, a solution of 5,5-dimethy1-1,4,5,6-tetrahydrocyclopentadieno[b]pyrrole-2-carbohydrazide (2.09 g, 10.5 mmol), triethyl orthoformate (3.11 g, 21.0 mmol) in DMF(8 mL) was reacted at 160 C for 16 hours. The reaction was cooled to room temperature, filtered, and washed with methanol, and the filter cake was collected, and dried in vacuum under reduced pressure to give the target product (1.65 g, yield 77%). [M+H] 204.1 Step 3: 4-chloro-2-(7,7-dimethyl-1-oxo-1,6,7,8-tetrahydro-2H-cyclopentale1,51pyrrolo11,2-di 11,2,41triazin-2-yOnicatinaldehyde The intermediate 1-75 was prepared with 7,7-dimethy1-7,8-dihydro-2H-cyclopenta[4,5]pyrrolo[1,2-d][1.2,4]triazin-1(611)-one and corresponding reagents according to the corresponding steps of intermediate I-1. [M+H] 343.1 The intermediates in the following table were prepared with corresponding materials and reagents according to the preparation steps of intermediate 1-75:
LC-MS
Intermediate Structural formula 1M+1-11+
1,y N
1-82 1).3211¨\
357.1 a N

1-85 arrri 342.8 1-86 ' ,- 343.0 ,N

1-87 325.0 1-88 328.8 I

N
1-89 343.0 N
1-94 ciJ7 347.0 Intermediate 1-83 2-(4-ch loro-3-(fl uor omethyl)pyridin-2-y1)-7,7-dimethy1-7,8-dihydro-2H-cyclopenta[4,51pyrrolo[1,2-alpyrazin-1(6H)-one ,oOHõOW
Step i I Step 2 Step 3 CI Br -)10.Ci.1,Br .41 N
,F jsy_ ,F
\
CI Br -11%.
--y ci N 1%1 Step 1: (2-bromo-4-chloropyridin-3-yl)methanol At 0-5 C, to a solution of 2-bromo-4-chloronicotinaldehyde (2.7 g, 12.2 mmol) in dichloromethane (30 mL) and methanol (10 mL) was added sodium borohydride (325 mg, 8.6 mmol), and stirred at this temperature for 30 minutes. The reaction was quenched by adding water to the reaction solution, and extracted with dichloromethane, the organic phase was collected, and concentrated in vacuum under reduced pressure, and the resulting residue was purified with silica gel column chromatography (petroleum ether/ethyl acetate) to give the target product (2.5 g, yield 92%).
Step 2: (2-bromo-4-chloropyridin-3-yl)methyl methanesulfonate At 0-5 C, to a solution of (2-bromo-4-chloropyridin-3-y1) methanol (1.0 g, 4.5 mmol) in dichloromethane (30 mL) was added methanesulfonyl chloride (573 mg, 5.0 mmol), and stirred at this temperature for 30 minutes. The reaction was quenched by adding water to the reaction solution, and extracted with dichloromethane, the organic phase was collected, and dried with anhydrous sodium sulfate. The reaction solution was filtered, and the filtrate was collected, concentrated in vacuum under reduced pressure to give the target product (1.35 g, yield 100%), which was directly used in the next step. [M+H] 299.9, 301.9 Step 3: 2-bromo-4-chloro-3-(fluoromethyl)pyridine To a solution of (2-bromo-4-chloropyridin-3-y1) methyl methanesulfonate (1.35 g, 5.0 mmol) in dried tetrahydrofuran (20 mL) was added 1M tetrabutylammonium fluoride/tetrahydrofuran (5.0 mL, 5.0 mmol), and stirred at 65 C for 2 hours.
The reaction was quenched by adding water to the reaction solution, and extracted with ethyl acetate, the organic phase was collected, and concentrated in vacuum under reduced pressure, and the resulting residue was treated with silica gel column chromatography (petroleum ether/ethyl acetate) to give the target product (700 mg, yield 62%). [M+H] 223.9, 225.9 2-(4-chloro-3-(fluoromethyl) pyridin-2-y1)-7,7-dimethy1-7,8-dihydro-2H-cyclopenta [4,5]pyrrolo[1,2-c]pyrazin-1(6H)-one was prepared with corresponding materials and reagents according to preparation step 8 of intermediate 1-1. [M+H] 346.1 Intermediate 1-91 4-c h loro-2-(1 0-flu oro- I -oxo-6,7,8,9-tetrahydropyrazino[1,2-alindo1-2(1H)-yl)nicotinaldehyde Step y1-1115) HN Step 2 HN \ ) .õõ
a a F 0 F
O
_1"`
No r Step 1: Ethyl 3-fluoro-1H-indo1-2-carboxylate To a solution of ethyl 1H-indo1-2-carboxylate (35.0 g, 185 mmol) in acetonitrile (1.75 L) was added 1-chloromethy1-4-fluoro-1,4-diazobicyclo[2.2.2]octanedi (tetrafluorobotic acid)salt (65.5 g, 1185 mmol), and stirred at room temperature for 45 minutes. The reaction was quenched by adding saturated brine, the organic phase was collected, and concentrated in vacuum under reduced pressure, and the resulting residue was purified with silica gel column chromatography (petroleum ether/ethyl acetate) to give the target product (18.0 g, yield 47%).
Step 2: Ethyl 3-fluoro-4,5,6,7-tetrahydro-1H-indo1-2-carboxylate To a solution of ethyl 3-fluoro-1H-indo1-2-carboxylate (10.5 g, 50.7 mmol) in acetic acid (210 mL) was added platinum dioxide (1.57 g, 1185 mmol). Under stirring at room temperature, the reaction solution was introduced with hydrogen, and reacted for 8 hours.
The reaction solution was filtered, the filtrate was collected, and concentrated in vacuum under reduced pressure, and the resulting residue was diluted by adding water, and neutralized to pH = 8 with aqueous ammonia. The reaction solution was extracted with ethyl acetate, and the organic phase was collected, and concentrated in vacuum under reduced pressure, to give the target product (10.5 g, yield 98%). [M+H] 212.0 4-chloro-2-(10-fluoro-1-oxo-6,7,8,9-tetrahydropyrazino[1,2-c]indol-2(1H)-y1) nicotinaldehyde was prepared with corresponding materials and reagents according to preparation steps 5-8 of intermediate I-1. [M+Hr 346.0 Intermediate 1-92 (RS)-2-(4-chloro.3-pyridine carboxaldehyde-2-y1)-7,7-dimethy1-1-oxo-1,6,7,8-tetrahydro-2H-cyclopenta[4,51pyrrolo[1,2-alpyrazin-6-y1 acetate 4,0 \
õ160( CI N CI N
I

To a solution of intermediate 1-55 (1.0 g, 3.0 mmol) in 1,4-dioxane (15 mL) was added lead acetate (2.0 g, 4.5 mmol), and the reaction was stirred at room temperature for 3 hours. The reaction solution was concentrated in vacuum under reduced pressure, and the resulting residue was diluted by adding water, and neutralized to pH = 8 with aqueous ammonia.
The reaction solution was extracted with ethyl acetate, the organic phase was collected, and concentrated in vacuum under reduced pressure, and the resulting residue was purified with silica gel column chromatography (methanol/water) to give the target product (600 fig, yield 50%). [M+H] 400.0 Intermediate 1-99 (5-bromo-2'-(7,7-dimethyl-l-oxo-1,6,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo [1,2-01pyrazin-2-y1)-1-methy1-6-oxo-1,6-dihyd ro-I3,4'-bispyridin1-3'-yl)m ethyl acetate + OH ,,,OAcr,N

BrI N
Br HO" N

Under nitrogen, a solution of 3-bromo-5-iodo-1-methylpridin-2(1H)-one (626 mg, 2.0 mmol), intermediate 1-4 (790 mg, 2.0 mmol), Pd(dppf)Cl2 CH2C12 (162 mg, 0.20 mmol), Xphos (94 mg, 0.20 mmol) and potassium phosphate (848 mg, 4.0 mmol) in acetonitrile (40 mL) and water (2 mL) was reacted at 30 C for 3 hours. The reaction solution was concentrated in vacuum under reduced pressure, and the resulting residue was purified with silica gel column chromatography (methanol/water) to give the target product. [M+H] 537.1, 539.1 intermediate 1-107 N-(5-bromo-l-methyl-2-oxo-1,2-dihydropyridin-3-yl)propanamide fi ==`,,--I+

Under nitrogen, to a solution of 3-amino-5-bromo-1-methylpyridin-2(1H)-one (609 mg, 3.0 mmol), propionyl chloride (416 mg, 4.5 mmol) in dichloromethane (20 mL) was dropwise added triethylamine (455 mg, 4.5 mmol), and reacted at room temperature for 1 hour.
The reaction solution was concentrated in vacuum under reduced pressure, and the resulting residue was purified with silica gel column chromatography (methanol/dichloromethane) to give the target product. [M+H] 259.0,261.0 The intermediates in the following table were prepared with corresponding materials and reagents according to the preparation steps of intermediate 1-107:
Structural LC-MS Structural LC-MS
Intermediate Intermediate formula M+111+ formula I
M+111+
0Nõ, 259.0, I
285.0, I-108HNBr 261.0 1-127 Br 287.0 cyLo 1-128 HN).õJ.Br 307.0, 309.0 o Compound 1 2-(5-((5-(ethyl (2-methoxyethyl)amino)pyridin-2-yl)amino)-3.-(hydroxymethyl)-1-methyl-6-oxo-1,6-dihydro-13,41.-bispyridin]-2'-y1)-7,7-dimethyl-7,8-dihydro-2H-cyclopenta14,51pyrrolo[1,2-a]pyrazin-1(6H)-one - Br I-4;LN OH C)AcreN-Cf-- Step 1 HO sy '0 rOAcii",N .prd /1-,e) (3.'N Step 2 11.,.,-;.4 8 rki :L
Lo Step 1: Acetic acid (2'-(7,7-dimethy1-1-oxo-1,6,7,8-tetrahydro-2H-cyclopenta[4,51pyrrolo[1,2-alpyrazin-2-y1)-5-05-(ethyl (2-methoxyethyl)amino)pyridin-2-yl)amino)-1-methyl-6-oxo-1,6-dihydro-I3,4'-bispyridini-Y-y1)methyl ester Under nitrogen, to a solution of intermediate 1-3 (126 mg, 0.33 mmol) and intermediate 1-4 (134 mg, 0.33 mmol) in 1,4-dioxane (5.0 mL) and water (0.5 mL) was added Xphos (31 mg, 0.066 mmol), Pd(dppf)C12 CH2C12 (27 mg, 0.033 mmol) and potassium phosphate trihydrate (264 mg, 0.99 mmol). The mixture was reacted at 100 C for 4 hours, and then cooled to room temperature. The reaction solution was concentrated in vacuum under reduced pressure, and the resulting residue was purified with silica gel column chromatography (methanol/water) to give the target product. [M+H] 652.3 Step 2: 2-(5-((5-(ethyl (2-methoxyethyl)amino)pyridin-2-y1)amino)-3'-(hydroxymethyl)-1-methyl-6-oxo-1,6-dihydro-I3,4'-bispyridin1-2'-y1)-7,7-dimeth7+.1-7,8-dihydro-cyclopenta[4,51pyrrolo[1,2-alpyrazin-1(6H)-one To a solution of acetic acid (2'-(7,7-dimethy1-1-oxo-1,6,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-y1)-5-05-(ethyl (2-methoxyethyl)amino)pyridin-2-yl)amino)-1-methy1-6-oxo-1,6-dihydro-[3,4'-bispyridin]-3t-yOmethyl ester obtained from step 1 in methanol (5 mL) was added potassium carbonate (137 mg, 0.99 mmol), which was reacted at room temperature for 2 hours. The reaction solution was concentrated in vacuum under reduced pressure, and the resulting residue was purified with thin layer chromatography (methanol/dichloromethane = 1/20) to give the target product (100 mg, two-step yield 50%).
[M+H] 610.3. 1HNMR (400 MHz, CD30D): 8.57-8.51 (m, 1H), 8.42-8.37 (m, 1H), 7.77-7.74 (m, 1H), 7.60-7.57 (m, 1H), 7.48-7.45 (m, 1H), 7.23-7.19 (m, 2H), 7.01-6.97 (m, 1H), 6.95-6.91 (m, 1H), 6.80-6.76 (m, 1H), 4.61-4.57 (m, 1H), 4.50-4.45 (m, 1H), 3.69 (s, 3H), 3.53-3.50 (m, 2H), 3.44-3.40 (m, 2H), 3.39- 3.34 (m, 2H), 3.32 (s, 3H), 2.78-2.69 (m, 2H), 2.66-2.57 (m, 2H), 1.30-1.27 (m, 6H), 1.13-1.08 (m, 3H).
The compounds in the following table were prepared with corresponding intermediates and reagents according to the preparation steps of compound 1:

LC-MS
Compound Structural formula , IILNNIR
Intermediate c) .

3 i 528.2 1H NMR (400 MHz, CD30D): 6 8.55 (d, J = 5.1 Hz, 1H), 8.39 (s, 1H), 7.73 1-5 and 1-4 b.) ,-.
-.
ONi rOH .r..ict (d, J = 5.1 Hz, 1H), 7.59 (s, 1H), 7.22 (d, J = 5.9 Hz, 1H), 6.92 (s, 1H), 6.81 a.
4.
HINNY
tli --k.,..;õ NO (d, J = 6.0 Hz, 1H), 4.84-4.78 (m, 1H), 4.54-4.49 (m, 1H), 4.46-4.40 (in, w en (----N
14.4i 2H), 3.64 (s, 3H), 2.80-2.70 (m, 2H), 2.62 (s, 2H), 1.57-1.49 (m, 3H), 1.31-C 1.27 (in, 6H).
4 i 0xN rOH crs:IL 542.2 'FL NMR (400 MHz, CD30D): 8 8.53 (d, J = 5.1 Hz, 1H), 8.39 (s, 1H), 7.71 1-6 and 1-4 --, (d, J = 5.1 Hz, 1H), 7.57 (s, 1H), 7.20 (d, J = 5.9 Hz, 1H), 6.91 (s, 1H), 6.80 =N '1'1 (d, J = 5.9 Hz, 1H), 4.85-4.78 (m, 2H), 4.53-4.46 (m, 1H), 3.63 (s, 3H), -4 2.79-2.69 (m, 2H), 2.61 (s, 2H), 1.61-1.53 (m, 6H), 1.31-1.26 (m, 6H).
.....cist o I 678.3 ' FINMR (400 MHz, CD30D): 8 8.66-8.60 (m, 2H), 8.10 (d, J = 2.7 Hz, 1H), 1-7 and 1-4 ...
.., ,... 0 N.r, orrIsi--.
.
w 7.69 (d, J = 5.1 Hz, 1H), 7.57-7.51 (in, 1H), 7.25-7.15 (in, 2H), 6.93 (s, 1H), ..
4.
:7.N I .... 6.82 (d, J = 5.9 Hz, 1H), 4.83-4.78 (m, 1H), 4.76- 4.62 (m, 5H), 4.57-4.50 .
.

y On, 1H), 3.89 (s, 3H), 3.85-3.75 (m, 1H), 3.38-3.33 (in, 1H), 3.04-2.97 (m, .
e 1H), 2.83-2.73 (m, 4H), 2.65-2.56 (m, 3H), 2.09-1.95 (in, 1H), 1.31-1.28 (m, ..
6H), 0.95-0.89 (m, 6H).

o 6 4 541.2 'FINMR (400 MHz, CD30D/CDC13): 8 8.52 (d, J =
5.1 Hz, 1H), 7.89 (s, 1-8 and 1-4 ti:IN,I,6NrS:1- 1H), 7.72-7.66 (n, 1H), 7.51 (d, J = 5.1 Hz, 1H), 7.43-7.38 (m, 1H), 7.07 (d, el\14 I ..N J = 6.0 Hz, 1H), 6.99(s, 1H), 6.65 (d, J = 5.9 Hz, 1H), 4.79-4.71 (m, 1H), mu --"C" 4.52-4.43 (m, 2H), 3.70 (s, 3H), 2.78-2.69 (m, 2H), 2.61 (s, 2H), 1.59-1.54 n i-3 n (in, 6H), 1.29-1.26 (m, 6H).

"
=
r.) ...

-a c, oe c, ,:.-.

7 i 542.2 1H NMR (400 MHz, CD30D/C
DC13): 8 8.60 (d, J = 5.1 Hz, 1H), 7.97 (s, 1-9 and 1-4 111), 7.71-7.67 (in,2H), 7.10-7.04 (m, 1H), 6.97 (s, 1H), 6.68 (d, J = 5.9 Hz, ;(1,14 '''"
1H), 4.84-4.74 (m, 1H), 4.59-4.54 (m, 2H), 3.89 (s, 31-1), 2.78-2.68 (m, 2H), 0 ---.1--N 2.61 (s, 2H), 1.60-1.55 (m, 6H), 1.29-1.27 (m, 6H). o b.) ,-.
-.
8 I 665.3 'FINMR (400 MHz, CD3OD
): 5 8.68 (d, J = 2.2 Hz, 1H), 8.53 (d, J = 5.1 1-10 and 1-4 g;
ON ) . ., . , : . . a 6, ro) = ii 1 r. , , , i ____3, ,.) Hz, 11-1), 7.95 (d, J = 2.8 Hz, 1H), 7.57 (d, J = 5.1 Hz, 1H), 7.52 (d, J =
2.2 w en .. ---I--HP? i 7 2 1 ,.. N 0 Hz, 1H), 7.46-7.41 (m, 1H), 7.21 (d, J = 5.9 Hz, 1H), 7.02 (d, J = 8.9 Hz, 1H), 6.93 (s, 1H), 6.80-6.76 (m, 1H), 4.63-4.41 (m, 2H), 3.68 (s, 3H), 3.60-(50 3.50 (m, 211), 3.44-3.39 (m, 1H), 3.37-3.33 (m, 3H), 3.09-2.96 (m, 2H), N 2.80-2.72 (m, 3H), 2.71-2.65 (m, 1H), 2.64-2.54 (m, 5H), 2.38-2.27 (m, 1H), 1) 1.31-1.25 (m, 6H), 0.92 (d, J = 6.3 Hz, 3H).
o., 9 i 649.3 'H NMR (400 MHz, CD30D):
5 7.85-7.79 (m, 1H), 7.72 (d, J = 5.1 Hz, 1H), 1-11 and 1-4 p o , .
7.09 (d, J = 2.8 Hz, 1H), 6.76 (d, J = 5.1 Hz, 1H), 6.68 (d, J = 2.0 Hz, 1H) .
.., 171 ."1,N I N 0 6.60-6.53 (in, 111), 6.43-6.36 (m, 1H), 6.21-6.16 (m, 1H), 6.11 (s, 111), 6.01- .
.
i 5.94 (m, 1H), 3.94-3.86 (in, 2H), 3.84-3.75 (m, 3H), 3.71-3.63 (m, 1H), 2.87 " .
(s, 311), 2.78-2.66 (m, 1H), 2.36-2.30 (m, 4H), 2.00-1.87 (m, 2H), 1.85-1.78 (N) (m, 2H), 1.73-1.66 (m, 4H), 0.50-0.44 (m, 6H).
z ON10 1 608.3 'FINMR (400 MHz, CD30D):
5 8.66 (s, 1H), 8.54 (s, 1H), 7.92 (s, 1H), 1-12 and 1-4 ,,1 Nr.,,,,,N \
7.62-7.48 (m, 2H), 7.41 (d, J = 7.3 Hz, 1H), 7.22 (d, J = 5.8 Hz, 1H), 7.03 HN ====, .
I .-N 0 I (d, J = 8.8 Hz, 1H), 6.94 (s, 1H), 6.78 (d, J =
5.8 Hz, 1H), 4.60 (d, J = 12.0 ..
le)--- -N
...1) i Hz, 1H), 4.49 (d, J = 12.1 Hz, 1H), 3.91-3.62 (m, 6H), 3.58-3.45 (m, 2H), v n N

3.3.11-2.96 (in, 211), 2.80- 2.68 (m, 211), 2.65-2.58 (s, 2H), 1.33-1.26(m, n 6H), 0.95 (d, J = 6.3 Hz, 3H).

r.) =
"
...

-a c, oe c, ,:.-.

1 11 i 677.3 'H NMR (400 MHz, CD30D): 6 8.55 (d, J = 5.0 Hz, 1H), 8.37-8.30 (m, 1H), 1-13 and 1-4 0 N i OHN.....:\
7.93-7.80 On, 1H), 7.45-7.36 (m, 2H), 7.24-7.17 (m, 1H), 6.97 (d, J = 8.8 HN 1( .**--Hz, 1H), 6.93-6.88 (m, 1H), 6.85-6.81 (m, 1H), 4.72-4.38 (m, 6H), 3.75-3.65 1 )4 (m, 3H), 3.53-3.37 (in, 2H), 3.09-2.95 (m, 2H), 2.78-2.66 (in, 2H), 2.62-2.51 b.) ,-.
, ,-.
(m, 3H), 2.50-2.39 (m, 2/1), 2.22-2.10 (m, 4H), 1.27 (d, J = 7.9 Hz, 6H), a.
0.98-0.88 (m, 3H).
w N
Vs CI o --- \ m, 619.1 'H NMR (400 MHz, CD30D): 6 8.56 (m, 1H), 8.49 (m, 1H), 8.34 (s, 1H), 1-15 and 1-4 r N
8.03 (m, 1H), 7.61 (m, 1H), 7.17 (m, 1H), 6.91 (s, 1H), 6.79 (m, 1H), 5.86 EHN
I .-'N 0 (s, 1H), 4.72 (in, 2H), 4.62 (m, 2H), 4.50 (in, 2H), 4.04 (m, 2H), 3.73 (m, N
1H), 3.56 (m, 2H), 2.83 (m, 2H), 2.71 (m, 2H), 2.59 (m, 214), 1.26 (m, 6H).
N-) o d0 ..1:1 t; al 14 .1 678.3 Ili NMR (400 MHz, CD30D): 6 8.64-8.59 (m, 1H), 8.55 (s, 1H), 8.07-7.99 1-16 and 1-4 I-0~
oN 0 ss 01-y7¨N ip .
1 (m, 1H), 7.72-7.67 (m, 1H), 7.48-7.42 (m, 1H), 7.23-7.19 On, 1H), 7.18-7.12 2 , N
---to FEN i -, (m, 1H), 6.92 (s, 1H), 6.84-6.78 (m, 1H), 4.79-4.74 (m, 1H), 4.73-4.68 (m, .

..,ti ' ,N 0 =
1 211), 4.66-4.62 (m, 1H), 4.61-4.57 (m, 1H), 4.56-4.49 (m, 111), 4.36-4.27 (m, 4-,.
2H), 3.77 -3.62 (m, 1H), 3.55-3.47 On, 1H), 3.22-3.06 (m, 2H), 2.79-2.67 .(s)) (m, 2H), 2.66-2.56 (m, 3H), 2.53-2.45 (m, 1H), 2.39-2.33 (m, 2H), 1.45-1.39 N
.K* (m, 3H), 1.31-1.25 (m, 6H), 1.08-0.99 (m, 3H).
15 I 0 c.6-11 581.2 ' NMR (400 MHz, CD30D): 6 8.56-8.48 (m, 1H), 8.17-8.11 (m, 1H), 7.60- 1-17 and 1-4 ......N 1 ONt1 7.51 (m, 1H), 7.48-7.41 (m, 1H), 7.25-7.18 (m, 1H), 6.92 (s, 1H), 6.80-6.75 v n "====N wi On, 1H), 6.51 (s, 1H), 4.61-4.43 (m, 2H), 4.29-4.22 On, 2H), 3.84-3.74 (m, =F -- .57 (m, (m, (s, 7 (s, Q
2H), 3.6 3H), 3.09 3H), 2.78-2.68 2H), 2.66-2 2H), 1.30- )..) 0 ,i) =
k..) 1.27 (m, 6H).
...

-a c, oe c, ,:.-.

' 16 Ni11 ofi ,,. 577.1 ifl NMR (400 MHz, CD30D): 8 8.59 (d, J = 5.0 Hz, 1H), 8.51 (s, 1H), 8.36 1-18 and 1-4 -, 1 (s, 1H), 8.06 (s, 1H), 7.64 (d, J = 5.1 Hz, 1H), 7.21 (d, J = 5.9 Hz, 1H),6.92 HN 1 1 (s, 1H), 6.80 (d, J = 5.6 Hz, 1H), 5.89 (s, 1H), 4.52-4.48 (m, 2H), 4.07-4.05 0 N
k.4 I ..=

pti (in, 2H), 3.64-3.62 (m, 2H), 2.94-2.92 (m, 2H), 2.78- 2.66 (m, 2H), 2.65- o b.) ,-.
-.
N-) ,-.
2.55 (m, 2H), 2.47 (s, 3H), 1.28-1.26 (m, 6H).
a.
4.

w 17 r---1 563.1 1H NMR (400 MHz, CD30D): 8 8.60 (d, J = 5.0 Hz, 1H),8.51 (d, J = 1.3 1-19 and 1-4 N., N OH
1 CN \ Hz, 1H), 8.37 (s, 1H), 8.02 (d, J = 1.3 Hz, 1H), 7.64 (d, J = 5.1 Hz, 1H), 7.21 HN I (d, J = 6.0 Hz, 1H), 6.92 (s, 1F1), 6.80 (d, J
= 5.9 Hz, 1H), 5.89 (s, 1H), 4.57-A ..14 0 µ PI 4.46 (m, 2H), 4.05-3.93 (m, 4H), 3.23 (t, J =
5.6 Hz, 2H), 2.79-2.55 (m, 4H), HN--) 1.30-1.26 (in, 6H).
18 f=r1 N .i_ 551.2 'H NMR (400 MHz, CD30D): 8 8.53 (d, J = 5.1 Hz, 1H), 8.47 (d, J = 1.2 1-20 and 1-4 HN%,. N 01.44,..; rLc.__ Hz, 1H), 8.32 (s, 1H), 7.92 (s, 1H), 7.58 (d, J = 5.1 Hz, 1H), 7.53 (d, J =
1.2 0 I Hz, 1H), 7.15 (d, J = 5.9 Hz, 1H), 6.85 (s, 1H), 6.72 (d, J = 5.9 Hz, 1H), ..?, ..1"
I.+ N¨N 4.54- 4.33 (m, 3H), 2.72-2.60 (m, 2H), 2.59-2.48 (m, 2H), 1.55-1.42 (m, .."
w ---c z 6H), 1.25-1.15 (m, 6H).
.
..) 19 I 663.3 tH NMR (400 MHz, CD30D): 8 8.70-8.68 (m, 1H), 8.57 (d, J = 5.1 Hz, 1H), 1-14 and 1-4 1-114....
.
(:) ,I N 0H C-rt4 p-'.0 --. 7.98-7.96 (m, 1H), 7.61 (d, J = 5.1 Hz, 1H), 7.56-7.54 (m, 1H), 7.48-7.44 .
I
. .... . . . ,i4 1 (in, 1H), 7.24 (d, J = 5.9 Hz, 1H), 7.06-7.04 (m, 1H), 6.96 (s, 1H), 6.81 (d, J
1 i = 5.9 Hz, 1H), 4.76-4.60 (m, 5H), 4.534.50 (m, 1H), 3.70 (s, 3H), 3.55-3.51 I
===e:,,) (m, 2H), 3.15-3.03 (m, 2H), 2.82-2.70 (m, 2H), 2.65-2.63 (m, 2H), 2.62-2.55 6 (m, 1H), 2.50-2.48 (m, 2H), 2.25-2.21 (in, 1H), 1.33-1.29 (m, 6H), 0.99 (d, J
= 6.4 Hz, 3H).
mig n n r.) =
r.) ....
..r.:
-a c, oe c, ,:.-.

I 20 1 . 1 OH 664.3 'H NMR (400 MHz, CD30D): 6 8.45 (d, J = 5.1 Hz, 1H), 8.02-7.98 (m, 1H), 1-22 and 1-4 ,..0 rz.,-, .. .1, \
7.85-7.83 (in, 1H), 7.67-7.65 (m, 1H), 7.55 (s, 1H),7.42-7.37 (m, 1H), 7.12 I i , N 0 (d, J = 5.9 Hz, 1H), 6.84 (s, 1H), 6.70 (d, J = 5.9 Hz, 1H), 4.64-4.45 (m, 5H), k.,) ..:-.. fl 4.40-4.36 (m, 1H), 3.66-3.64 (m, 1H), 3.55 (s, 3H), 3.44-3.34 (in, 1H), 3.09-b.) ,-.
-.
,-.
3.01 (m, 2H), 2.70-2.59 (m, 2H), 2.52 - 2.50 (m, 3H), 2.38-2.25 (m, 2H), a.
4.
-.1 2.21-2.19 (m, 1H), 1.21-1.19 (m, 6H), 0.95 (d, J = 6.3 Hz, 3H).
w en o 21 -psi- , 673.3 ill NMR (400 MHz, CD30D): 6 8.73-8.71 (m, 1H), 8.64-8.60 (m, 2H), 8.40 1-23 and 1-4 HN ) try tiS* (s, 111), 7.99 (d, J = 2.6 Hz, 111), 7.67 (d, J = 5.0 Hz, 111), 7.49-7.45 (m, 1H), li ..N 0 7.22 (d, J = 5.9 Hz, 1H), 7.08 (d, J = 8.9 Hz, 1H), 6.95 (s, 1H), 6.83 (d, J =
====, 1 5.9 Hz, 1H), 4.74-4.70 (m, 2H), 4.66-4.48 (m, 4H), 3.63-3.46 (m, 2H), 3.17-3.03 (in, 2H), 2.81-2.69 (m, 2H), 2.63-2.59 (m, 2H), 2.56-2.54 (m, 2H), 4tN) 2.44-2.42 (m, 1H), 2.28-2.26 (m, 1H), 1.32-1.28 (m, 6H), 1.01 (d, J = 6.3 0 .
Hz, 3H).
o 01-w z ' 22 6*
I 664.3 'H NMR (400 MHz, CD30D): 6 8.53 (d, J = 5.0 Hz, 1H), 8.46 (s, 1H), 7.94 1-24 and 1-4 0 N,N OH
(d, J = 2.7 Hz, 1H), 7.59 (d, J = 5.1 Hz, 1H), 7.39-7.35 (m, 1H), 7.12-7.08 HN
..N 0 (m, 2H), 6.84 (s, 1H), 6.72 (d, J = 5.9 Hz, 1H), 4.65-4.45 (m, 6H), 3.66-3.55 .
z (m, 1H), 3.45-3.36 (in, 1H), 3.07-3.03 (m, 2H), 2.71-2.59 (m, 2H), 2.53-2.50 =
(m, 3H), 2.41-2.39 (m, 1H), 2.29-2.25 (m, 2H), 1.22-1.18 (m, 6H), 0.95 (d, J
= 6.4 Hz, 3H).

mo n n r.) =
r.) ....
..r.:

c, oe c, :.-:

I 23 -JF'690.3 'H NMR (400 MHz, CD30D): 8 8.59 (d, J = 5.1 Hz, 1H), 8.33 (s, 1H), 8.04 1-25 and 1-4 RI:7:N
OH ¨
,....- NI \ (s, 1H), 7.97 (d, J = 2.7 Hz, 11-1), 7.66 (d, J = 5.0 Hz, 1H), 7.48-7.46 (m, 1H), HN---- N --- 7.28-7.18 (m, 2H), 7.06 (d, J = 8.9 Hz, 1H), 6.93 (s, 1H), 6.80 (d, J = 5.4 Hz, k.,) ........ ti4 IN 0 i 1H), 4.72-4.68 (in, 2H), 4.64-4.56 (m, 3H), 4.50-4.48 (m, 1H), 3.59-3.45 (m, b.) -..
,-.
2H), 3.16-3.02 (m, 2H), 2.78-2.42 (m, 7H), 2.26-2.24 (m, 1H), 1.29-1.27 (m, a, 4.
..1 . ) 6H), 0.99 (d, J = 6.3 Hz, 3H). w en N

. .
1 24 I _ 527.2 'H NMR (400 MHz, CD30D): 8 8.54 (d, J = 5.1 Hz, 1H), 7.91 (s, 1H), 7.62- 1-26 and 1-4 oyN,I. i0Hr.1.-,NrS1 7.57 (m, 2H), 7.48-7.46 (m, 1H), 7.23 (d, J = 5.9 Hz, 1H), 6.94 (s, 1H), 6.77 ---.,- N 0 (d, J = 5.9 Hz, 1H), 4.56-4.47 (m, 2H), 4.38 (q, J = 7.3 Hz, 2H), 3.70 (s, 3H), 2.76-2.72 (m, 2H), 2.62-2.58 (m, 2H), 1.51 (t, J = 7.4 Hz, 3H), 1.30- 1.27 (4i (in, 6H).

25 I 528.2 1H NMR (400 MHz, CD30D): 8 8.60 (d, J = 5.1 Hz, 1H), 7.92 (s, 11-1), 7.69 1-27 and 1-4 ..,"1 ,... ON ,N
'8 ca ig µ40 I (d, J = 5.1 Hz, 11-1), 7.61 (s, 11-1), 7.21 (d, J = 5.9 Hz, 111), 6.92 (s, 111), 6.79 N ----HN i (d, J = 5.9 Hz, 1H), 4.72-4.70 (m, 1H), 4.51-4.49 (m, 1H), 4.41 (q, J = 7.3 69 ,.>"
' .41 0 ek-N
S
-1.1 Hz, 2H), 3.87 (s, 3H), 2.80-2.68 (m, 2H), 2.66-2.55 (m, 2H), 1.52 (t, J = 7.3 cN
Hz, 3H), 1.30-1.27 (m, 6H).
26 I 621.3 'FINMR (400 MHz, CD30D): 8 8.69 (d, J = 2.3 Hz, 111), 8.55 (d, J = 5.1 1-28 and 1-4 :N
N Hz, 1H), 7.96 (d, J = 2.7 Hz, 1H), 7.59 (d, J = 5.1 Hz, 1H), 7.53 (d, J =
2.3 ...,,j. Hz, 1H), 7.46-7.44 (m, 1H), 7.22 (d, J = 5.9 Hz, 1H), 7.03 (d, J = 8.9 Hz, .
Li) I 1H), 6.94 (s, 1H), 6.79 (d, J = 5.9 Hz, 1H), 4.63-4.42 (m, 2H), 3.70 (s, 3H), I t3.44-3.40 (m, 1H), 3.10-3.01 (m, 2H), 2.79-2.70 (in, 3H), 2.65-2.52 (m, 4H), n N i 2.36-2.27 (m, 4H), 1.31-1.27 (m, 6H), 0.94 (d, J = 6.4 Hz, 3H).
I i i n ¨
¨ 2 r.) =
r.) ....
..r.:

c, oe c, t.-:

I -77 i 677.3 'F1 NMR (400 MHz, CD30D): 8 8.73 (d, J = 2.2 Hz, 1H), 8.55 (d, J = 5.1 1-2 and 1-4, Oy...1,41,60HrN3:3 Hz, 1H), 8.00 (d, J = 2.6 Hz, 1H), 7.62-7.53 (m, 2H), 7.51-7.47 (m, 1H), Steps 5 HN..""--* 1 `,-rNils-o .. . . .. , j , , N 0 7.22 (d, J = 5.9 Hz, 1H), 7.04 (d, J = 8.9 Hz, 1H), 6.94 (s, 1H), 6.79 (d, J = k.) I
1.) . 5.9 Hz, 1H), 4.75-4.71 (m, 1H), 4.70-4.57 (m, 4H), 4.50-4.48 (m, 1H), 3.79--.
,-.
3.77 (m, 1H), 3.70 (s, 3H), 3.26-3.14 (m, 1H), 2.92-2.89 (m, 1H), 2.80-2.57 o, .1.
' -.1 N (m, 6H), 2.55-2.45 (m, 1H), 1.96-1.92 (m, 1H), 1.31-1.27 (m, 6H), 0.90-0.87 w en (m, 6H).
o _ 28 I 513.2 Ili NMR (400 MHz, CD30D): 8 8.52 (d, J = 5.1 Hz, 1H), 7.83 (s, 1H), 7.59- 1-29 and 1-4 0 N., OH ,...
r N \ 7.55 (m, 2H), 7.47-7.45 (m, 1H), 7.24-7.20 (m, 1H), 6.93-6.91 (m, 1H), HN

N ---I i 6.78-6.74 (m, 1H), 4.52-4.46 (m, 2H), 4.04 (s, 3H), 3.69 (s, 3H), 2.79-2.67 el.N,N (m, 211), 2.66-2.56 (m, 211), 1.29-1.26 (m, 611).
/N-N
29 I 514.2 'FINMR (400 MHz, CD30D): 8 8.59 (d, J = 5.0 Hz, 111), 7.86 (s, 1H), 7.68 1-30 and 1-4 0 o,õ,N.N orie,N ,,1-.
(d, J = 5.1 Hz, 1H), 7.61-7.59 (m, 1H), 7.22-7.20 (m, 1H), 6.91-6.59 (m, -'.
, liN:-;......)..y.cN,,,1317 I-; ; ' I
IF!), 6.81-6.76 (m, 1H), 4.74-4.46 (m, 2H), 4.07 (s, 3H), 3.86 (s, 3H), 2.78- ...
µs1.1 L-N b ro N-N 2.68 (m, 211), 2.66-2.56 (m, 2H), 1.30-1.28 (m, 611). e " /
.

30 I 581.2 'FINMR (400 MHz, CD30D): 8 8.55 (d, J = 5.2 Hz, 1H), 8.01 (s, 1H), 7.71 1-31 and 1-4 0N.I.N 4-' " ,01-y......N_ \
(d, J = 2.0 Hz, 1H), 7.59 (d, J = 5.2 Hz, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.24 ---H ' '')'& 0 (d, J = 6.0 Hz, 1H), 6.94 (s, 1H), 6.78 (d, J = 6.0 Hz, 1H), 5.28-5.21 (m, 2H), coLN ,N
N-1:1 4.58-4.46 (m, 2H), 3.71 (s, 3H), 2.75 (d, J = 2.8 Hz, 2H), 2.63 (s, 211), 1.29 S\--F (d, J = 5.6 Hz, 611).
F F
31 I 545.2 ' NMR (400 MHz, CD30D): 8 8.56 (d, J = 5.2 Hz, 1H), 8.16 (d, J = 2.4 1-32 and 1-4 71.5 oy:: 1 044---El Hz, 1H), 7.58 (d, J = 5.2 Hz, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.48 (m, 1H), n tiN 1 c., 7.23 (d, J = 6.0 Hz, 111), 6.94 (s, 111), 6.8.0 (d, J = 6.0 Hz, 1H), 4.79-4.76 k..) (.. = , N 0 SN-4 (m, 1H), 4.65-4.47 (m, 5H), 3.71 (s, 3H), 2.75 (d, J = 3.2 Hz, 2H), 2.63 (s F
, 21-1), 1.29 (d, J = 6.4 Hz, 611).
" ...
..r.:

c, Ge c, ,:.-.

32 1 546.2 'H NMR (400 MHz, CD30D-d4): 8 8.63 (d, J = 4.8 Hz, 1H), 8.04 (s, 1H), 1-33 and 1-4 0õN.,N 01-kr,c6 7.68 (d, J = 4.8 Hz, 1H), 7.57 (s, 111), 7.23 (d, J = 6.0 Hz, 1H), 6.93 (s, 1H), 6.82 (d, J = 6.0 Hz, 1H), 4.82-4.73 (m, 3H), 4.70-4.66 (m, 1H), 4.64-4.60 k..) -N (11, 1H), 4.52 (d, J = 12.4 Hz, 1H), 3.89 (s, 3H), 2.75 (d, J = 2.4 Hz, 2H), b.) I-.
FSN
2.63 (s, 211), 1.30 (d, J = 5.2 Hz, 6H).
.....
,-.
ct, 4.

Ca 33 1 582.1 'NMR (400 MHz, CD30D-d4): 8 8.62 (d, J = 5.2 Hz, 1H), 8.04 (s, 1H), 1-34 and 1-4 N
Vs N,N OH ,r7rN S1--FI 7.75 (s, 1H), 7.70 (d, J = 5.2 Hz, 1H), 7.22 (d, J = 6.0 Hz, 1H), 6.93 (s, 1H), :
=L'r4 6.81 (d, J = 6.0 Hz, 1H), 5.33-5.27 (m, 2H), 4.74 (d, J = 12.4 Hz, 1H), 4.51 t -N (d, J = 12.8 Hz, 1H), 3.89 (s, 3H), 2.74 (s, 2H), 2.62 (s, 2H), 1.29 (d, J = 4.8 ..--F Hz, 6H).
F F
34 1 663.3 41 NMR (400 MHz, CD30D):
8 8.87 (d, J = 2.4 Hz, 1H), 8.56 (d, J = 5.2 1-35 and 1-4 0 N OH,r,;-:,;13 i ,_ 4 ---\ Hz, 1H), 8.18 (d, J = 2.4 Hz, 1H), 7.62-7.56 (m, 3H), 7.23 (d, J = 6.0 Hz, .

1H), 7.12 (d, J = 8.8 Hz, 111), 6.94 (s, 1H), 6.79 (d, J = 6.0 Hz, 1H), 4.76-..,"
.
.,..y '8 4.

.., 1 4.73 (m, 3H), 4.66-4.59 (m, 3H), 4.49 (d, J = 12.4 Hz, 1H), 3.74 (d, J = 5.2 N.
i.) .
0 N ) Hz, 1H), 3.72 (s, 3H), 3.71-3.67 (in, 114), 3.21 (s, 214), 2.83-2.78 (m, 2H), " 2.75 (d, J = 3.2 Hz, 2H), 2.63 (s, 211), 1.29 (d, J = 6.4 Hz, 6H).
i ' N
17;
35 1 594.2 'FINMR (400 MHz, CD30D):
8 8.55 (d, J = 5.2 Hz, 1H), 8.51 (d, J = 2.0 1-36 and 1-4 N i r,O OH--,,,N \
Hz, 1H), 7.58 (d, J = 5.2 Hz, 1H), 7.53 (d, J = 2.4 Hz, 111), 7.48 (d, J = 2.0 HN 1 :, Hz, 1H), 7.23 (d, J = 5.6 Hz, 1H), 7.02-6.90 (m, 3H), 6.79 (d, J = 5.6 Hz, "... i 1H), 4.60 (d, J = 12.0 Hz, 1H), 4.48 (d, J = 12.0 Hz, 1H),4.36-4.31 (m, 111), 4.14-4.04 (m, 2H), 3.70 (s, 3H), 3.63-3.60 (m, 2H), 3.34 (s, 3H), 2.74 (d, J =
v n A
.3 Y 3.6 Hz, 2H), 2.62 (s, 2H), 1.29 (d, J = 6.4 Hz, 6H). n t4 0.,..
=
N
....

GC
..7., 36 I 0 N ,OH.r..N
646.3 'H NMR (400 MHz, CD30D): 6 8.83 (d, J = 2.0 Hz, 1H), 8.56 (d, .1= 5.2 1-37 and 1-4 ,_\
I Hz, 1H), 8.29 (s, 1H), 7.73-7.71(m, 11-1), 7.61 (d, J = 5.2 Hz, 1H), 7.57 (d, J
HN N

I = 2.0 Hz, 1H), 7.23 (d, J =
6.0 Hz, 1H), 7.04 (d, J = 8.4 Hz, 111), 6.94 (s, k.4 , N 0 N-.
1H), 6.80 (d, J = 6.0 Hz, 1H), 6.10 (s, 1H), 4.75-4.72 (m, 2H), 4.68-4.60 (m, 3H), 4.50 (d, J = 12.4 Hz, 1H), 3.71 (s, 3H), 3.68-3.62 (m, 1H), 3.07 (s, 2H), N 2.74 (d, J = 3.2 Hz, 2H), 2.65-2.56 (In, 6H), 1.29 (d, J = 6.4 Hz, 6H). o b.) ,-..
.....
,-..
cr.
4.
=====1 W
<1 37 641.3 'NMR (400 MHz, CD30D): 6 8.89 (d, J = 2.4 Hz, 1H), 8.57 (d, J = 5.2 1-38 and 1-4 0 AI OH (;) N,-FI
1 C---32 Hz, 1H), 8.50 (d, J = 2.4 Hz, 1H), 7.91-7.88 (m, 1H), 7.62-7.58 (m, 4H), HN
I 7.50 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 6.0 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), / N "''' N 0 i 6.94 (s, 1H), 6.81 (d, J =
6.0 Hz, 1H), 5.12-5.09 (m, 2H), 4.79-4.75 (m, 2H), 4.63 (d, J = 12.0 Hz, 1H), 4.51 (d, J = 12.0 Hz, 1H), 4.34-4.27 (m, 1H), 3.72 110 (s, 311), 2.74 (d, J = 3.6 Hz, 2H), 2.62 (s, 2H), 1.29 (d, .1 - 6.8 Hz, 6H).
.."
'4-1 ),a .

1 o ' 40 1 -474.2 1FINMR (400 MHz, CD30D): 6 8.52 (d, J - 4.8Hz, 1H), 7.53 (d, J - 5.2 Hz, 1-40 and 1-4 2 OHNrcrlyir-1H), 7.23-7.21 (m, 2H), 6.93 (s, 1H), 6.76 (d, J = 6.0 Hz, 1H), 6.66 (d, J =
1:', ---2,N 0 2.0 Hz, 1H), 4.54 (d, J = 11.6 Hz, 1H), 4.46 (d, J = 12.0 Hz, 1H), 3.64 (s, 3H), 3.61-3.56 (m, 1H), 2.74 (d, .1 = 3.6 Hz, 2H), 2.62 (s, 2H), 1.29 (d, J =
6.4 Hz, 6H), 1.23 (m, 6H).
41 594.3 'Li NMR (400 MHz, CD30D): 6 8.62 (d, J = 2.0 Hz, 1H), 8.54 (d, J = 5.2 1-41 and 1-4 o rL, o ,..,. I H,,c(NLS- 1¨
Hz, 1H), 7.64 (d, J = 2.4 Hz, 1H), 7.57 (d, J = 4.8 Hz, 1H), 7.50 (d, J = 1.6 00 .., j Hz, 1H), 7.25-7.16 (m, 2H), 6.99 (d, J = 8.8 Hz, 1H), 6.93 (s, 1H), 6.78 (d, J
= 5.6 Hz, 1H), 4.84-4.81 (m, 2H), 4.64-4.57 (m, 3H), 4.52-4.40 (m, 2H), 3.69 (s, 31-1), 2.78 (s, 3H), 2.74 (d, J = 3.2 Hz, 2H), 2.62 (s, 21-), 1.29 (d, J =
(-5 k=-) =
k=.) ...
'µICIo 6.0 Hz, 6H).

GC
Z, 42 572.4 'NMR (400 MHz, CD30D): 8 8.58-8.53 (m, 1H), 8.43-8.38 (m, 1H), 7.76- 142 and 1-4 0 N _...-, LA, I \ 7.73 (in, 1H), 7.62-7.59 (m, 1H), 7.24-7.20 (m, 1H), 6.95-6.90 (m, 1H), HN' ....N \ N .-- FI

f..1,...N 1!...õ,;.N 0 6.84-6.79 (m, 1H), 4.86-4.81 (m, 2H), 4.54-4.49 (m, 1H), 3.82-3.74 (m, 1H), k..) o N-41 3.72-3.68 (m, 1H), 3.65 (s, 3H), 3.29-3.27 (m, 3H), 2.79-2.70 (in, 2H), 2.67- b.) ,-.
1 2.58 (m, 2H), 1.59-1.54 (m, 3H), 1.31-1.28 (n, 6H). , ,-.
C' 4.

-.1 \
ta en 43 I 664.3 'H NMR (400 MHz, CD30D):
6 8.57-8.53 (in, 1H), 8.53-8.50 (m, 1H), 8.11- 1-43 and 1-4 N OH
c-0., 1 rõ .r..NSIL
'-- 8.06 (m, 1H), 7.85-7.81 (m, 1H), 7.58-7.55 (in, 111), 7.52-7.49 (m, 1H), HN
7.24-7.20 (m, 1H), 6.95-6.92 (m, 1H), 6.81-6.76 (in, 1H), 4.72-4.68 (m, 2H), Nyl-J 4.67-4.64 (m, 1H), 4.62-4.57 (m, 2H), 4.51-4.46 (m, 1H), 4.41-4.34 (m, 1H), 3.82-3.75 (in, 1H), 3.70 (s, 3H), 3.50-3.43 (m, 1H), 3.18-3.11 (m, 1H), 2.84-( ) N 2.79 (m, 1H), 2.78-2.69 (in, 2H), 2.67-2.58 (m, 3H), 2.26-2.18 (m, 1H), 6 2.09-2.00 (m, 1H), 1.31-1.28 (m, 6H), 1.23-1.19 (m, 3H). 0 .
44 I 664.3 '11 NMR (400 MHz, CD30D): 6 8.81-8.75 (in, 1H), 8.58-8.54 (m, 1H), 8.33- 1-44 and 1-4 ..,"
,...
.."
õOH

ta ...... 1 r Nre-^:irSi-8.28 (in, 2H), 7.62-7.60 (m. 1H), 7.59-7.57 (in, 1H), 7.25-7.20 (m, 1H), .

co I 6.96-6.92 (m, 1H), 6.82-6.77 (m, 1H), 4.73-4.68 (m, 2H), 4.66-4.57 (m, 3H), ,.>
, NH*1-N
, N 0 0 co y 4.52-4.46 (m, 1H), 3.71 (s, 3H), 3.65-3.58 (m, 1H). 3.55-3.46 (m, 1H), 3.19- ' z 3.07 (m, 2H), 2.80-2.69 (m, 2H), 2.67-2.58 (m, 2H), 2.58-2.50 (in, 2H), ( ) N 2.46-2.38 (m, 1H), 2.33-2.24 (m, 1H), 1.31-1.28 (m, 6H), 1.07-1.01 (m, 3H).

o 45 I 608.3 'FINMR (400 MHz, CD30D):
a 8.57-8.51 (in, 1H), 8.40-8.34 (m, 1H), 7.73- 1-45 and 1-4 0 N (.01ir, `.. 1 . N --- 7.69 (in, 1H), 7.60-7.57 (m, 1H), 7.48-7.44 (in, 1H), 7.25-7.20 (m, 1H), HN 1 \
IV
...-N o 7.13-7.08 (m, 1H), 6.98-6.89 (m, 2H), 6.81-6.75 (in, 1H), 4.60-4.57 (m, 1H), n 1 4.50-4.45 (m, 1H), 3.95-3.90 (m, 1H), 3.81-3.75 (m, 1H), 3.70 (s, 3H), 3.50- n -.

HNo 3.44 (m, 1H), 3.41-3.35 (m, 1H), 3.26-3.20 (m, 1H), 2.96-2.69 (in, 2H), )..) =
k..) 2.67-2.34 (m, 2H), 2.07-2.00 (in, 1H), 1.81-1.71 (m, 1H), 1.69-1.59 (m, 1H), ....

-.) . 1.56-1.46 (m, 1H), 1.31-1.28 (m, 6H). c, i c, ,:.-.

46 I 638.3 ' NMR (400 MHz, CD30D):
8 8.56-8.51 (m, 1H), 8.38-8.34 (m, 1H), 7.72- 1-46 and 1-4 O ,:i 1 oH,;126 F1 7.68 (in, 1H), 7.59-7.56 (m, 1H), 7.47-7.43 (m, 1H), 7.24-7.20 (m, 1H), . 1 7.12-7.07 (m, 1H), 6.97-6.88 (m, 2H), 6.81-6.75 (m, 1H), 4.61-4.57 (m, 1H), 4.50-4.45 (m, 1H), 4.12-4.06 (m, 1H), 3.69 (s, 3H), 3.52-3.49 (in, 2H), 3.40-k..) o b.) i...
.-i...
HN , 3.35 (m, 1H), 3.34-3.32 (m, 1H), 3.11-3.03 (m, 1H), 2.96-2.69 (m, 2H), a.
4.
2.67-2.34 (m, 2H), 2.20-2.12 (m, 1H), 1.76-1.67 (m, 1H), 1.48-1.38 (m, 2H), ...) w en OH 1.32-1.28 (m, 6H).
47 I ..\ 622.3 Ili NMR (400 MHz, CD30D): 8 8.96-8.92 (m, 1H), 8.57-8.55 (m, 1H), 8.34- 1-47 and 1-4 8.32 (m, 111), 7.71-7.67 (in, 1H), 7.63-7.61 (m, 1H), 7.60-7.57 (m, 1H), HN N 7.24-7.22 (m, 1H), 7.12-7.09 (m, 1H), 6.95-6.92 (in, 1H), 6.80-6.78 (m, 1H), ., N 0 L) 4.62-4.58 (m, 1H), 4.51-4.47 (m, 1H), 3.75-3.58 (m, 11H), 2.80-2.69 (m, 0 N 2H), 2.67-2.58 (m, 2H), 1.30-1.28 (m, 6H).
') Lo o w 48 I 635.3 'FINMR (400 MHz, CD30D):
8 8.95-8.92 (m, 1H), 8.57-8.54 (m, 1H), 8.33- 1-48 and 1-4 ..,"
-..."
4. o ..: i oticrNSL
8.30 (in, 1H), 7.69-7.66 (m, 1H), 7.63-7.61 (in, 1H), 7.59-7.57 (m, 1H), ig 4.
.>
HN

7.24-7.21 (m, 1H), 7.11-7.08 (m, 1H), 6.94-6.92 (m, 1H), 6.80-6.77 (m, 1H), " 1.) / N 1 .N 0 I
4.62-4.57 (m, 1H), 4.51-4.46 (m, 1H), 3.76-3.56 (m, 7H), 2.79-2.69 (m, 2H), 2.66-2.58 (m, 2H), 2.54-2.40 (m, 4H), 2.31 (s, 3H), 1.30-1.27 (m, 6H).
.

I-2.66-2.58 o N'Th 49 o ri, 650.3 'H NMR (400 MHz, CD30D):
8 8.64-8.60 (m, 1H), 8.60-8.58 (m, 1H), 8.06- 1-49 and 1-4 HNTiCCr""Nc51-- 8.01 (m, 1H), 7.72-7.68 (m, 1H), 7.48-7.43 (m, 1H), 7.23-7.19 (m, 11-1), I
7.18-7.14 (In, 1H), 6.94-6.91 (m, 11-1), 6.82-6.79 (m, 1H), 4.74-4.68 (m, 3H), ,, 4.66-4.57 (m, 2H), 4.53-4.47 (m, 1H), 3.76-3.65 (m, 1H), 3.53-3.45 (m, 1H), mig n N 3.21-3.06 (m, 2H), 2.79-2.67 (m, 2H), 2.66-2.61 (in, 211), 2.61-2.55 (m, 1H), 2.51-2.45 (m, 1H), 2.38-2.31 (m, 2H), 1.29-1.28 (m, 6H), 1.06-1.01 (m, 3H).
n r.) .
"
...
.
.
c, c, ..-.

50 I 596.3 'H NMR (400 MHz, CD30D):
6 8.56-8.51 (m, 1H), 8.45-8.40(m, 1H), 7.78- 1-50 and 1-4 :.1 (D,..,..,,,co.);-,N......H.).31 7.74 (m, 1H), 7.60-7.56 (m, 1H), 7.49-7.45 (m, 1H), 7.25-7.20 (m, 2H), 1N,N i ,N 0 7.01-6.96 (m, 1H), 6.95-6.91 (m, 1H), 6.80-6.75 (m, 1H), 4.62-4.56 (m, 1H), k.4 Y 4.50-4.44 (m, 1H), 3.69 (s, 3H), 3.56-3.52 (m, 2H), 3.47-3.42 (m, 2H), 3.32 b.) ,-.
-.
,-.
(s, 3H), 2.92 (s, 3H), 2.78-2.69 (m, 2H), 2.66-2.57 (m, 2H), 1.30-1.26 (m, a.
4.
,..N.,1 Lo 6H).
w en I
51 624.3 ' NMR (400 MHz, CD30D):
6 8.57-8.52 (m, 1H), 8.51-8.45 (m, 1H), 7.89- 1-51 and 1-4 0 1 OHN,irctgef 11 7.81 (m, 1H), 7.61-7.57 (m, 1H), 7.50-7.46 (m, 1H), 7.34-7.29 (in, 1H), ,..iiiN 1 ::-N 0 7.24-7.20 (m, 1H), 7.02-6.97 (in, 1H), 6.96-6.90 (m, 1H), 6.81-6.75 (m, 1H), 1 4.62-4.56 (m, 1H), 4.51-4.45 (m, 1H), 3.89-3.79 (m, 1H), 3.70 (s, 3H), 3.46--.
3.40 (in, 2H), 3.35-3.31 (m, 5H), 2.79-2.69 (m, 2H), 2.66-2.57 (m, 2H), 1.30-1.27 (m, 6H), 1.17-1.11 (m, 6H).

?
.
,., I-.4 1-, 80 I 663.3 III NMR (400 MHz, CD30D): 6 8.68 (d, J = 2.1 Hz, 1H), 8.55 (d, J = 5.1 1-76 and 1-4 0"
4. OH61¨
p.
to Nrc:Hz, 1H), 7.95 (d, J = 2.7 Hz, 1H), 7.59 (d, J = 5.1 Hz, 1H), 7.53 (d, J =
2.2 Ig HN 1 Hz, 1H), 7.46-7.42 (m, 1H), 7.22 (d, J = 5.9 Hz, 1H), 7.03 (d, J = 8.9 Hz, ,,, ,,, ......ti ,...N 0 ' co I
=
1H), 6.93 (s, 1H), 6.78 (d, J = 5.9 Hz, 1H), 4.75-4.41 (m, 6H), 3.70 (s, 3H), ...
,,, .16) 3.53-2.49 (in, 2H), 3.14-2.96 (m, 2H), 2.80-2.68 (m, 2H), 2.65-2.40 (m, 5H), N 2.22-2.18 (m, 1H), 1.30-1.28 (m, 6H), 0.97 (d, J
= 6.3 Hz, 3H).

o 81 512.2 Ili NMR (400 MHz, CD30D/CDC13=1/1) 6 8.55-8.50 (m, 1H),7.91-7.87 1-100 and 1-4 o ..!11 oiiNc, Nr6 -(m, 1H), 7.54-7.52 (m, 1H), 7.48-7.45 (m, 1H), 7.34-7.31 (m, 1H), 7.11-7.07 HN 1 -...
V
1 ,N 0 (m, 1H), 6.97-6.93 (in, 1H), 6.71-6.66 (m, 1H), 6.02-5.97 (m, 1H), 4.56-4.50 n .3 N5 (m, 1H), 4.46-4.39 (m, 1H), 3.77 (s, 3H), 3.68 (s, 3H), 2.76-2.66 (in, 2H), n 2.65-2.55 (m, 2H), 1.29-1.25 (m, 6H).
" =
t.) ...

c, Ge c, ,:.-.

82 I -L- 526.2 'H NMR (400 MHz, CD30D) 8 8.55-8.48 (in, 1H), 7.92-7.85 (m, 1H), 7.58- 1-101 and 1-4 ON OH_õ--,,, N-c.... 7.53 (in, 1H), 7.43-7.38 (m, 11-1), 7.23-7.18 (m, lff), 6.96-6.88 (m, 1H), 6.80-6.73 (m, 1H), 5.89-5.82 (m, 1H), 4.59-4.53 (m, 1H), 4.49-4.42 (m, 1H), k..) p rlN / 3.67 (s, 3H), 3.64 (s, 3H), 2.79-2.67 (m, 2H), 2.66-2.55 (m, 2H), 2.22 (s, b.) ,-.
, ,-.
3H), 1.30-1.26 (m, 6H).
a.
4.
83 ! 510.2 'I NMR (400 MHz, CD30D) 8 8.93 (d, J = 2.4 Hz, 1H), 8.66 (s, 1H), 8.56 1-102 and 1-4 till (d, J = 5.2 Hz, 1H), 8.26 (d, J = 6.0 Hz, 1H), 7.72 (d, J = 2.4 Hz, 1H), 7.58 HN ''''= .---I (d, J = 4.8 Hz, 1H), 7.22 (d, J = 6.0 Hz, 1H), 7.07 (d, J = 6.0 Hz, 11-1), 6.93 (131 (s, 111), 6.79 (d, J = 6.0 Hz, 1H), 4.59 (d, J = 12.0 Hz, 1H), 4.48 (d, J = 12.0 Hz, 1H), 3.70 (s, 3H), 2.73 (d, J = 3.2 Hz, 2H), 2.62 (s, 2H), 1.28 (d, J =
6.4 Hz, 6H).
84 I 510.2 'FINMR (400 MHz, CD30D) 8 8.95 (d, J = 1.9 Hz, 1H), 8.64 (d, J = 4.4 Hz, 1-103 and 1-4 I

1H), 8.55 (d, J = 5.2 Hz, 114), 7.77 (d, J = 2.0 Hz, 1H), 7.60 (d, J = 4.8 Hz,cr'r-S1-- w HN '-' "s- --.
I 1H), 7.48-7.45 (m, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.14 (d, J = 6.4 Hz, 1H), ..,"
,... ,N 0 e"
ON N, gi 6.95 (s, 1H), 6.73 (d, J =
6.0 Hz, 1H), 4.56 (d, J = 12.0Hz, 1H), 4.45 (d, J = z .:.
12.4 Hz, 1H), 3.73 (s, 3H), 2.72 (s, 2H), 2.61 (s, 2H), 1.28 (d, J = 3.6 Hz, 6H).

I-85 I 524.2 'FI NMR (400 MHz,CD30D) 8 8.93 (d, J = 2.4 Hz, 1H), 8.56 (d, J = 5.2 Hz, 1-104 and 1-4 0 N, ..1, 0Hr:1;6f- 1H), 7.71 (d, J
= 2.4 Hz, 1H), 7.62 (d, J = 5.2 Hz, 1H), 7.40 (d, J = 4.0 Hz, 2H), 7.22 (d, J = 6.0 Hz, 1H), 6.93 (s, 1H), 6.78 (d, J = 5.6Hz, 1H), 4.59 (d, J
.,N 0 =-, 'N
= 12.0 Hz, 1H), 4.49 (d, J = 12.1 Hz, 1H), 3.72 (s, 31-1), 2.74 (d, J = 2.6 Hz, 2H), 2.62 (s, 2H), 2.53 (s, 3H), 1.29 (d, J = 5.6 Hz, 6H).
86 1 512.2 1H NMR (400 MHz, CD30D) 8 8.53-8.48 (in, 1H), 7.76-7.70 (m, 1H), 7.53- 1-105 and 1-4 75 0 ,,,N 1 OHNictr =i 7.46 (m, 2H), 7.32-7.28 (m, 1H), 7.24-7.20 (m, 1I1), 7.06-7.01 (m, 1H), HN
n I e :N 0 6.95-6.90 (m, 1H), 6.77-6.72 (m, 1H), 4.55-4.42 (m, 2H), 3.83 (s, 3H), 3.68 2 =
(s, 3H), 2.79-2.68 (m, 2H), 2.67-2.56 (m, 2H), 1.30-1.27 (m, 6H).
..."
/N-N

-a c, oe c, ,:.-.

.1-106 and 1-4 0 N ,--, 513.2 tH NMR (400 MHz, CD30D) 8 8.58-8.53 (m, 1H), 8.16-8.11 On, 1H), 7.63-I-ir NP---7.57 On, 2H), 7.24-7.20 (m, 1H), 6.95-6.91 On, 1H), 6.80-6.77 (n, 1H), HN 1 N'IrL-'' ,õ...,,,N 0 6.06-6.01 (m, 1H), 4.60-4.44 (m, 211), 3.69 (s, 3H), 2.81-2.68 (m, 2H), 2.67- 64 2.56 (n, 2H), 2.33 (s, 3H), 1.30-1.27 (m, 6H).
,-.
, ,-.
.
a, 88 I 0H 488.2 IFINMR (400 MHz, CD30D) 8 8.62-8.57 (m, 111), 8.57-8.52 (m :i , 1H), 7.82- 1-107 and 1-4 :-o T ...,c,Ni....
en y N, 7.77 (n, 1H), 7.55-7.52 (m, 1H), 7.24-7.19 (m, III), 6.95-6.90 (m, 1H), .. --1 6.80-6.75 (in, 111), 4.56-4.41 (m, 2H), 3.67 (s, 311), 2.78-2.68 (m, 211), 2.66-2.56 (m, 2H), 2.52-2.45 (in, 2H), 1.30-1.26 (n, 611), 1.21-1.15 (m, 3H).
89 ni 500.2 'H NMR (400 MHz, CD30D) 8 8.59-8.50 (m, 2H), 7.82-7.75 (in, 1H), 7.55- 1-108 and 1-4 1 0Hc...rptp-7.50 On, 1H), 7.24-7.17 (m, 1H), 6.95-6.88 (m, 1H), 6.80-6.73 (m, 1H), HN -..' -s=-= N ....' 4.57-4.39 (in, 211), 3.68 (s, 3H), 2.78-2.68 (m, 2H), 2.66-2.56 (m, 2H), 2.01-1.88 (m, 1H), 1.31-1.25 (in, 6H), 0.97-0.85 (n, 4H).

.
90 1 527.2 1H NMR (400 MHz, CD30D/CDC13=1/1) 8 8.74-8.69 (n, 1H), 8.57-8.52 1-109 and 1-4 .
...
.., o N
OH2SD. L. p.
i-i ), (m, 1H), 8.07-8.03 (m, 111), 7.62-7.61 (n, 1H), 7.55-7.53 (m, 1H), 7.40-7.34 ... 0 i.) (n, 1H), 7.11-7.07 (m, 1H), 7.00-6.94 (n, 2H), 6.71-6.68 (in, 1H), 4.56-4.41 .
i.) =Nj ' N
" I (n, 2H), 3.70 (s, 3H), 2.77-2.65 On, 2H), 2.65-2.56 (m, 2H), 1.29-1.25 (m, 0 .
F 6H).
p4;
91 1 677.3 IFINMR (400 MHz, CD30D) 8 8.64-8.60 (n, 1H), 8.56-8.52 (m, 1H), 7.92- 1-110 and 1-4 N r wr----;13 Hox3,0,. 0 ..,, 7.87 (m, 1H), 7.60-7.56 (m, 1H), 7.52-7.49 (m, 1H), 7.42-7.37 On, 1H), . I 7.23-7.20 (m, 11-1), 7.04-6.98 On, 1H), 6.94-6.91 (n, 1H), 6.80-6.75 (m, 1H), p, ..-N
4.73-4.67 (m, 2H), 4.65-4.59 (m, 2H), 4.58-4.56 (n, 1H), 4.51-4.44 (m, 11-1), 3.69 (s, 314), 3.52-3.45 (in, 1H), 3.41-3.34 (n, 111), 3.16-3.05 (in, 2H), 2.78- v 6 2.68 (n, 2H), 2.66-2.54 (m, 3H), 2.50-2.38 (n, 2H), 2.35-2.26 (in, 1H), n .3 o 1.70- 1.58 (m, 1H), 1.42-1.33 (m, 1H), 1.30-1.26 (m, 6H), 0.86-0.079 (in, n 3H).
"
=
t.) ...
..=
-a c, oe c, ,:.-.

94 1 664.3 IFINMR (400 MHz, CD30D):
8 8.67 (d, J = 2.1 Hz, 1H), 8.55 (d, J = 5.1 1-111 and 1-4 0 _.....N i r OHNcl,riSt Hz, 1H), 7.94 (d, J = 2.7 Hz, 1H), 7.58 (d, J = 5.1 Hz, 1H), 7.52 (d, J = 2.3 H N
, N 0 Hz, 1H), 7.44 (dd, J = 9.0, 2.8 Hz, 1H), 7.22 (d, J = 5.9 Hz, 1H), 7.02 (d, J = "
=-,- 7 o i b.) 8.9 Hz, 1H), 6.93 (s, 111), 6.78 (d, J = 5.9 Hz, 1H), 4.72-4.46 (m, 6H), 3.70 -.
,-.
a.
ts)) (s, 3H), 3.53-3.45 (m, 1H), 3.12-2.99 (m, 2H), 2.79-2.68 (m, 2H), 2.65-2.60 4.
-.1 t.e N (m, 2H), 2.60-2.54 (m,1H), 2.51-2.43 (m, 1H), 2.26-2.16 (m, 1H), 1.28 (d, J cn ,,k D
= 6.3 Hz, 6H), 0.96 (d, J = 6.3 Hz, 3H).
V
95 i 677.4 1-112 and 1-4 0N OH , r.---' ri P..... 11-1 NMR (400 MHz, CD30D) 8 8.75 (d, J = 2.3 Hz, 1H), 8.56 (d, J = 5.1 Hz, Ny.1=----1H), 8.02 (d, J = 2.6 Hz, 1H), 7.60 (d, J = 5.1 Hz, 1H), 7.55 (d, J = 2.2 Hz, õ.....1-õN I ,N 0 IH), 7.50-7.48 (m, 1H), 7.23 (d, J = 5.9 Hz, 1H), 7.00 (d, J = 8.8 Hz, 1H), 6.94 (s, 1H), 6.79 (d, J = 5.9 Hz, 1H), 4.70-4.50 (m, 6H), 3.71 (s, 3H), 3.45-.43 (m, 1H), 3.15-3.13 (m, 2H), 2.79-2.68 (m, 2H), 2.67-2.57 (m, 2H), ,., ,...
N
4. 6 2.44-2.42 (m, 2H), 2.25-2.15 (m, 2H), 1.29-1.27 (m, 6H), 1.07-1.05 (m, 6H).
co 0 97 D 13 0 666.3 1H NMR (400 MHz, CD30D) 8 8.68 (d, J = 2.1 Hz, 1H), 8.55 (d, J = 5.0 Hz, 1-81 and 1-4 2 :
...,. ..... 0 i N..,,;(73 1H), 7.95 (d, J = 2.7 Hz, 1H), 7.59 (d, J = 5.2 Hz, 111), 7.52 (d, J = 2.3 Hz, .
HN I 1H), 7.44 (dd, J = 8.9, 2.8 Hz, 1H), 7.22 (d, J = 5.9 Hz, 1H), 7.03 (d, J = 8.9 ,N 0 --.11 i Hz, 1H), 6.93 (s, 1H), 6.78 (d, J = 5.9 Hz, 11-1), 4.72-4.47 (m, 6H), 3.56-3.44 , (m, 2H), 3.14-3.01 (m, 2H), 2.79-2.69 (m, 2H), 2.66-2.59 (m, 2H), 2.59-2.54 ' tN) (m, 1H), 2.50-2.43 (in, 2H), 2.26-2.14 (m, 1H), 1.29 (d, J = 6.4 Hz, 6H), 6 0.97 (d, J = 6.3 Hz, 3H).
o mo 99 1 _ 625.3 111 NMR (400 MHz, CD30D) 8 8.57-8.52 (m, 11-1), 8.12-8.07 (m, 1H), 7.58- 1465 and 1-4 n .3 OHNctSf 7.55 (m, 1H), 7.46-7.42 (m, 1H), 7.25-7.20 (m, 1H), 6.95-6.90 (in, 1H), n HN--1 ,Ni 0 6.81-6.75 (m, 1H), 6.27-6.21(m, 1H), 4.60-4.54 (in, 1H), 4.50-4.44 (m, 1H), "
=
t.) /,_ I 3.79 (s, 3H), 3.75-3.61 (m, 11H), 2.78-2.68 (rn, 2H), 2.66-2.56 (In, 2H), ...
N r---\

-a _I 2 i 1 1.30-1.7 (in, 614 c, Ge o c, i i ____ _ ,:....

1102 646.3 i , 1-113 and 1-4 0 4 OH 61 1 ' H NMR (400 MHz, CD301.3):
8 8.68 (d, J = 2.0 Hz, 1H), 8.55 (d, J = 5.1 rist- \
Hz, 1H), 7.94 (d, J = 2.5 11z, 1H), 7.59 (d, J = 5.1 Hz, 1H), 7.52 (d, J = 2.0 b.) ===== r. ii ' I
Hz, 1H), 7.43 (dd, J = 8.9, 2.8 Hz, 1H), 7.22 (d, J =
5.9 Hz, 1H), 7.02 (d, J = o k..) i..i 8.9 Hz, 1H), 6.93 (s, 1H), 6.78 (dd, J = 5.9, 0.6 Hz, 1H), 4.66-4.43 (m, 2H), -.
,-.
a, ) 3.75 -3.63 (m, 5H), 3.62-3.50 (m, 1H), 3.14-3.03 (m, 2H), 2.83-2.58 (m, 4.
..1 W
Eli 1 7H), 2.54-2.46 (m, 1H), 1.28 (d, J = 6.5 Hz, 6H), 0.97 (d, J = 6.4 Hz, 3H).
L't4 . 106 NI 595.3 1-41 and 1-1 c/14-- 1H NMR (400 MHz, CD30D/CDC13=2/1) 8 8.57-8.52 (m, 2H), 8.31-8.27 (m, 1H), 7.62-7.59 (m, 1H), 7.57-7.53 (m, 1H), 7.50-7.46 (m, 1H), 7.20-7.16 HN '''==

.. N 0 (in, 1H), 7.07-7.04 (m, 1H), 6.96-6.92 (m, 1H), 4.854.81 (m, 2H), 4.66-4.62 -. (m, 2H), 4.56-4.43 (m, 3H), 3.69 (s, 3H), 2.84-2.79 (m, 2H), 2.78 (s, 3H), '1'lo 2.66-2.60 (m, 2H), 1.30 (s, 6H).

,., ...
.
..1 .., 107 0 4 612.3 ' 1-115 and 1- .."
4.
..
oN \
.>
.0 -. 1 tH NMR (400 MHz, CD30D) 8 8.55-8.49 (m, 1H), 8.41-8.36 (m, 1H), 7.97- 114 .>
4 -, o HN
' N 0 7.90 (m, 11-0, 7.58-7.55 (m, 1H), 7.41-7.36 (m, 1H), 7.70-6.99 (m, 1H), 7 0 5.90-5.78 (in, 1H), 4.59-4.49 (m, 2H), 4.04-3.97 (m, 2H), 3.72-3.68 (m, 2H), .
N) 3.66 (s, 3H), 3.59-3.55 (m, 2H), 3.33 (s, 3H), 3.04-2.97 (m, 2H), 2.85-2.80 (m, 2H), 2.78-2.72 (in, 2H), 2.63 (s, 2H), 1.29 (s, 6H).
\
108 I 632.3 i 1-116 and 1-4 o ,.....r411 r,..orN,\ ... j H NMR (400 MHz, CD30D): 8 8.71 (d, J = 1.8 Hz, 1H), 8.55 (d, J = 5.1 HN I Hz, 1H), 7.94(d, J = 2.5 Hz, 1H), 7.58(d, .1- 5.2 Hz, 1H), 7.53 (d, J = 1.8 mig n Hz, 1H), 7.43 (dd, J = 8.8, 2.7 Hz, 1H), 7.22 (d, J = 5.9 Hz, 1H), 7.03 (d, 3=
n 8.9 Hz, 1H), 6.93 (s, 1H), 6.78 (d, J = 6.0 Hz, 1H), 4.64-4.45 (m, 2H), 3.70 (4) (s, 3H), 3.58- 3.33 (m, 4H), 3.15-3.09 (in, 3H), 2.79-2.69 (in, 2H), 2.66-2.55 )..) =
k..) ...
(m, 2H), 1.28 (d, J = 6.5 Hz, 6H), 0.98 (d, J = 6.4 Hz, 3H).

-.) c, Ge c, ,:.-.

109 1 675.3 'HNMR (400 MHz, CD30D):
8 8.52 (d, J = 5.0 Hz, 1H), 8.43 (s, IH), 7.63 1-117 and 1-4 o.õ.....,:,.f roHt.....\
(s, 1H), 7.56 (d, J = 5.1 Hz, 1H), 7.45 (d, J = 2.1 Hz, 111), 7.20 (d, J = 5.9 71,--:.--"MOLI o Hz, 1H), 7.08 (dd, J = 9.0, 2.8 Hz, 1H), 6.99 (d, J = 8.7 Hz, 1H), 6.92 (s, )4 o y 1H), 6.76 (d, J = 5.9 Hz, 1H), 4.77-4.67 (m, 4H), 4.60-4.44 (m, 2H), 4.24- b.) ,-.
, ,¨.
4.14 (m, 1H), 4.08-3.97 (m, 1H), 3.68 (s, 3H), 3.54-3.40 (m, 2H), 3.24-3.15 ON
4.
(N n (in, 111), 3.02-2.92 (m, 111), 2.77-2.69 (m, 211), 2.68 -2.57 (m, 3H), 2.29-c.) v=
N
2.16 On, 1H), 2.00-1.90 (m, 2H), 1.66-1.55 (m, 1H), 1.27 (d, J = 6.4 Hz, 6 6H).
o 110 0. rti 626.3 1H NMR (400 MHz, CD30D) 8 8.58-8.47 (m, 1H), 8.45-8.34(m, 1H), 7.99- 1-118 and!-T .88 (m, 1H), 7.61-7.51 On, 1H), 7.43-7.33 (m, 1H), 7.08-6.98 (m, 1H), t af:17(61¨

HN
- C T
,- N o 5.95-5.85 (m, 1H), 4.62-4.47 (m, 2H), 4.03-3.91 (in, 2H), 3.81-3.74 (m, 1H), ..._.1 N¨) 3.67 (s, 3H), 3.59-3.51 (m, 2H), 3.38-3.31 (m, 4H), 2.98-2.86 (m, 2H), 2.86- 0 (s, ..
,... 2.78 (m, 211), 2.73-2.65 (m, 1H), 2.65-2.58 (m, 2H), 1.43-1.36 (m, 31), 1.29 .
..,"
"
vs 0 6H).
4-' o \ .
.

625.3 1H NMR (400 MHz, CD30D) 8 8.55 (s, 1H), 8.02-7.91 (m, 111), 7.56 (s, 1-118 and 1-4 1 N.
co =
HN 1H), 7.41 (d, J = 1.9 Hz, 1H), 7.20 (d, J = 5.8 Hz, 1H), 6.92 (s, 1H), 6.76 (d, IN
I
, N o J= 5.8 Hz, 1H), 5.86 (s, 1H), 4.52-4.48 (m, 2H), 3.99-3.95 (m, 211), 3.84-...8111 3.72 (m, 1H), 3.67 (s, 3H), 3.59-3.46 (m, 211), 3.37-3.35 (m, 1H), 3.33 (s, :
3H), 2.97-2.83 (m, 2H), 2.78-2.56 (m, 51), 1.40 (d, J = 6.5 Hz, 3H), 1.29-1.26 (m, 611).
\
112 I ¨ 623.3 1-119 and 1-4 InO
IFINMR (400 MHz, CD30D) 8 8.49 (d, J = 4.6 Hz, 1H), 7.97 (d, J = 0.7 Hz, n HN
J = 18 7 1H = 1 d 4 1H H J = 7 I 1H), .53 (d, 5.0 z, ), 7.0 (, J .3 Hz, ), . (d, 5.9 Hz, ` n , N 0 _IN 1H), 6.91 (s, 1H), 6.75 (d, J = 5.9 Hz, 1H), 5.87 (s, 1H), 4.72-4.64 (m, 4/1), )..) =
k.) 7151 4.56-4.43 (m, 2H), 4.05-3.89 (m, 3H), 3.78-3.76 (m, 1H), 3.63 (s, 3H), 3.19- ...

0 3.09 (m, 1H), 2.82-2.54 (m, 5H), 1.27-1.23 (m, 9H). ¨a c, oe c, :.-:

_ .
I 115 625.2 1FI
1-120 and 1-4 -NMR (400 MHz, CD30D) 8 8.52 (d, J = 5.1 Hz, 111 1, 7.95 (d, J = 2.2 Hz, 1H), 7.56 (d, J = 5.1 Hz, 1H), 7.42 (d, J = 2.2 Hz, 111). 7.21 (d, J = 5.9 Hz, H"11.1,õN 1 ..,..N /or b.) 1H), 6.92 (s, 1H), 6.76 (d, J = 5.9 Hz, 1H), 5.84 (s, 1H), 4.58-4.42 (m, 21-1), o ri -\ -)' 3.98 (t, J = 5.5 Hz, 2H), 3.86-3.74 (m, 2H), 3.67 (s, 3H), 3.53-3.51 (m, 1H), b.) ,-..
-.
,-..
o --r 3.41-3.39 (m, 111), 3.32 (s, 3H), 3.11-2.91 (m, 3H), 2.79-2.67 (m, 2H), 2.67- 4.
G.) 0 2.55 (m, 211), 1.30-1.26 (m, 6H), 1.10 (d, J = 6.8 Hz, 311). v=
\
118 624.3 IHNMR (400 MHz, CD30D) 8 8.56-8.52 (m, 1H), 8.42-8.38 (in, 111), 7.98- 1-119 and 1-I N =-=\ 7.93 (m, 1H), 7.60-7.57 (m, 1H), 7.41-7.38 (m, 1H), 7.06-7.02 (m, 111), 114 ..,N 0 5.92-5.89 (m, 1H), 4.72-4.68 (m, 3H), 4.65-4.62 (m, 1H), 4.59-4.51 (m, 2H), ..._.N
N-N) 4.06-4.00 (m, 1H), 3.99-3.94 (m, 211), 3.84-3.78 (m, 1H), 3.68 (s, 3H), 3.21-3.15 (m, 1H), 2.86-2.79 (m, 3H), 2.66-2.62 (m, 2H), 1.30 (s, 6H), 1.29-1.27 do (m, 3H).

121 0 4 010.1,N --- 640.3 1-118 and 1- .
..1 I..
WI

41,-1:-...Y I H NMR (400 MHz, CD30D) 8 8.56-8.51 (m, 1H), 7.96-7.92 (m, 1H), 7.59- 121 ...
,...
HN I 7.57 (m, 1H), 7.42-7.38 (m, 1H), 7.06-7.02 (m, 1H), 5.93-5.89 (m, 111), .
....N 0 to 4.59-4.50 (m, 2H), 4.02-3.94 (m, 2H), 3.83-3.75 (m, 1H), 3.68 (s, 3H), 3.59-e 0 , 3.53 (m, 2H), 3.40-3.35 (m, 1H), 3.07-3.02 (m, 2H), 3.00-2.86 (m, 2H), ...
i 2.73-2.65 (m, 111), 2.63-2.60 (m, 5H), 1.43-1.38 (m, 3H). 1.31 (s, 611).
a I
\ I 1 122 I 610.3 i 1-122 and 1-0 N O., 1 IH NMR (400 MHz, CD30D) 8 8.56-8.51 (m, Ill), 8.42-8.38 (m, 11-1), 7.98-, I Z T 3S3L--HN I 1 7.94 (in, 1H), 7.60-7.56 (in, 1H), 7.42-7.38 (m, 111), 7.06-7.02 (in, 1H), 5.88-5.85 (m, 1H), 4.75-4.72 (m, 2H), 4.64-4.61 (m, 214), 4.58-4.52 (m, 2H), mo A
ci-N) 4.06-4.01 (m, 2H), 3.78-3.71 (m, 1H), 3.68 (s, 3H), 3.58-3.54 (m, 2H), 2.86-A
2.81 (In, 414), 2.65-2.62 (m, 2H), 1.30 (s, 6H).

k.) =
do k=.) ..

c, Ge c, 4.-..

124 I _ 609.3 1-122 and 1-4 O N., 11-1NMR (400 Mlit, CD30D) 6 8.56-8.50 (in, 1H), 7.99 (d, J = 2.2 Hz, 111), 7.57 (d, J = 5.1 Hz, 1H), 7.43 (d, J = 2.2 Hz, 1H), 7.21 (d, J = 5.9 Hz, 1H), p .N 0 k.) i 6.92 (s, 1H), 6.77 (d, J = 6.0 Hz, 1H), 5.91-5.84 (m, 1H), 4.75-4.46 (m, 6H), o b.) N--) ,¨.
4.03 (t, J = 5.6 Hz, 2H), 3.78-3.71 (m, 1H), 3.68 (s, 3H), 3.56 (s, 2H), 2.86--.
,-.
ON
4.
2.55 (m, 6H), 1.30-1.26 (m, 6H).
c.) Co-cn 125 523.2 IF1 NMR (400 MHz, CD30D) 6 8.72-8.66 (n, 1H), 8.58-8.52 (m, 1H), 8.05- 1-123 and 1-4 s.õ.. 4 1 HNic-"(6 8.00 (n, 1H), 7.60-7.57 (m, 1H), 7.55-7.52 (m,1H), 7.48-7.43 (m, 1H), HN---I 7.25-7.20 (m, 1H), 7.00-6.90 (m, 2H), 6.81-6.76 (m, 111), 4.62-4.57 (in, 1H), .,- N 0 =-",131 1 4.51-4.45 (m, 1H), 3.70 (s, 3H), 2.80-2.67 (m, 2H), 2.67-2.56 (m, 2H), 2.22 (s, 311), 1.30-1.27 (m, 611).
126 OH y..... 539.2 Ili NMR (400 MHz, CD30D) 6 8.67-8.62 (m, 1H), 8.57-8.52 (m, 1H), 7.93- 1-124 and 1-4 0 NrcrtS
7.88 (in, 1H), 7.59-7.56 (m, 1H), 7.52-7.49 (m, 1H), 7.31-7.27 (m, 1H), ..?, HN

sl I..I
õõ.... 14 GN 0 7.24-7.20 (m, 11-1), 7.04-6.99 (n, 1H), 6.95-6.91 (m, 1H), 6.80-6.76 (m, 1H), .
tn ...
t=.> 1 4.62-4.57 (m, 111), 4.51-4.44 On, 111), 3.79 (s, 311), 3.69 (s, 3H), 2.79-2.68 .
-..
.
(m, 2H), 2.66-2.57 (in, 2H), 1.30-1.26 (n, 6H).
.
.

130 I 514.0 'II NMR (400 MHz, CD30D) 6 8.64-8.59 (n, 1H), 8.58-8.53 (m, 111), 7.82- 1-127 and 1-4 7.76 (in, 11-1), 7.58-7.51 (m, 1H), 7.27-7.18 (n, 111), 6.96-6.90 (m, 1H), HN I

-N CI 6.81-6.75 (m, 1H), 4.59-4.49 (n, 1H), 4.49-4.39 (in, 1H), 3.67 (s, 3H), 3.43-3.37 (n, 1H), 2.79-2.69 (m, 2H), 2.67-2.56 (n, 2H), 2.39-2.27 (n, 2H), 2.26-2.17 (m, 2H), 2.10-1.97 (m, 1H), 1.96-1.81 (m, 1H), 1.30-1.26 (m, 6H).
131 1 536.0 'NMR (400 MHz, CD30D) 6 8.79-8.72 On, 1H), 8.61-8.54 On, 1H), 7.98- 1-128 and 1-4 HN,..
0 ,N 1.I,1OHN 321--FI 7.92 (n, 2H), 7.89-7.82 (m, 1H), 7.64-7.57 (m, 2H), 7.57-7.49 (m, 211), v n YL
.3 100I 0 ,--1,1 0 7.26-7.20 On, 1H), 6.93 (s, 1H), 6.83-6.76 On, 1H), 4.61-4.55 (m, 1H), 4.52- n 4.43 (n, 1H), 3.73 (s, 3H), 2.80-2.67 (n, 2H), 2.67-2.56 (m, 2H), 1.30-1.27 )..) =
k..) (m, 6H).
....

-.) c., Ge c., ,:.-.

0 N 1 0$---1 132 I 525.2 I i I H NMR (400 MHz, CD30D/CDC13=2/1) 8 8.98-8.94 (m, III), 8.61-8.56 1-104 and 1-i (n, 1H), 8.37-8.33 (m 114, 1H), 7.73-7.70 (m, 1H), 7.65-7.62 (m, 1H), 7.41-7.33 0 b.) ..,N 0 (iTI, 2H), 7.11-7.05 (m, I
H), 4.62-4.55 (m, 2H), 3.71 (s, 3H), 2.87-2.83 (m, =
b.) ,-.
2H), 2.69-2.64 (m, 2H), 2.53 (s, 3H), 1.30 (s, 6H).
-.
I-.
a.
4.
-.1 133 I 540.2 'H NMR (400 MHz, CD30D) 8 8.62-8.59(m, 1H), 8.54-8.51 (m, 1H), 8.41- 1-124 and I-bl 0 N., .,õOft,,r_ SL
I 7 N \ 8.38 (m, 1H), 7.92-7.89 (m, 1H), 7.59-7.56 (m, 1H), 7.48-7.45 (m, 1H), 114 --s- '.
N 0 7.29-7.25 (m, 1H), 7.05-7.02 (m, 1H), 7.02-6.98 (m, 1H), 4.60-4.52 (m, 2H), 3.79 (s, 3H), 3.68 (s, 3H), 2.86-2.79 (m, 2H), 2.65-2.60 (m, 211), 1.30 (s, o, 6H).

..,N 0Hr.c.r13-3 581.2 1F1 NMR (400 MHz, CD30D/CDC13=2/1) 8 8.59-8.54 (m, I H), 7.99-7.94 1-122 and 1-(m, 111), 7.59-7.56 (m, IH), 7.50-7.47 (m, 1H), 7.21-7.17 (m, 1H), 7.01-6.97 129 p (m, 1H), 6.78-6.72 (m, 1H), 5.90-5.86 (m, 1H), 4.80-4.76 (m, 2H), 4.69-4.65 ..
..
,., .
EN
.., ...
I-, (m, 2H), 4.60-4.55 (m, 1H), 4.50-4.45 (m, 1H), 4.12-4.05 (m, 2H), 3.82-3.75 e ...
cm c)) N:1) (m, 1H), 3.72 (s, 3H), 3.62-3.57 (m, 2H), 2.96-2.90 (in, 2H), 2.89-2.85 (in, " i.) i.) 211), .-. (m, 11), .-. (m, ).
.1.
do 284279 2 263254 2H

.
.
138 I 499.0 1-26 and 1- "
o ..,.. ,,..17-IN
1H NMR (400 MHz, CDC13) 8 8.52 (d, J = 3.6 Hz, IH), 7.79 (d, J = 2.2 Hz, HN I 111), 7.70 (s, I H), 7.57 (s, 1H), 7.43-7.38 (m, 211), 7.04 (s, 111), 6.95-6.92 et, 1;1 ...õ..õ-N 0 (m, 111), 6.61 (d, J = 3.9 Hz, 1H), 5.28-5.24 (m, 1H), 4.50-4.33 (m, 4H), ' \/N-N 3.70 (s, 311), 2.86-2.82 (m, 4H), 2.61-2.50 (m, 2H), 1.55 (t, J = 7.4 Hz, 3H).
v n i-3 n r.) =
r.) ....

-.) c, oe c, 4.-..

1139 1 595.2 1-36 and 1-O N Otir.r1 \
,. I 1H NMR (400 MHz, CD3OD) 5 8.56-8.52 (m, 1H), 8.49-8.46 (m, I H), 8.42- 114 N ---8.39 (in, 1H), 7.60-7.58 (m, 1H), 7.54-7.52 (m, 1H), 7.47-7.43 (m, 1H), 7.04 k.4 o I 1 (s, 1H), 6.99-6.93 (m, 2H), 4.62-4.51 (m, 2H), 4.36-4.29 (m, 1H), 4.10-4.04 b.) ,-.
N.
-.
,-.
(m, 2H), 3.69 (s, 3H), 3.63-3.59 (m, 2H), 3.31 (s, 3H), 2.85-2.82 (m, 2H), ON
A
4.
Y 2.65-2.62 (m, 2H), 1.30 (s, 6H).
w en 0, 140 I 620.2 1-130 and 1-4 ON 1 oH\
1H NMR (400 MHz, CD301)) 6 8.81-8.76(m, 1H), 8.58-8.52 (m, I H), 8.16-8 .11 (In, 1H), 7.71-7.67 (m, IH), 7.60-7.55 (m, 2H), 7.25-7.19 (m, 1H), ..,,,,1 N 0 ...,N; 7.08-7.02 (m, 1H), 6.93 (s, 1H), 6.81-6.75 (m, 1H), 4.76-4.71 (m, 2H), 4.62-4.58 (m, 1H), 4.52-4.46 (in, 3H), 3.88-3.80 (m, 1H), 3.78-3.71 (m, 3H), 3.70 N
(s, 3H), 3.28-3.24 (m, 2H), 2.79-2.68 (m, 2H), 2.66-2.56 (m, 2H), 1.29-1.26 o i..i (M, 6H).
..
sl I..

I..
n) 4, =
, I 621.2 1-130 and I- 7 e NMR (400 MHz, CD30D) ö 8.77-8.73 (m, 1H), 8.57-8.53 (in, 1H), 8.43-...
" N UN 0 8.39 (in, 1H), 8.16-8.11 (in, 1H), 7.70-7.67 (m, I H), 7.61-7.58 (in, 1H), 7.55-7.51 (in, 1H), 7.07-7.02 (m, 2H), 4.75-4.72 (m, 2H), 4.61-4.54 (m, 2H), ' i 4.52-4.48 (m, 2H), 3.87-3.81 (m, 1H), 3.78-3.71 (m, 3H), 3.70 (s, 3H), 3.28-N i 3.26 (m, 2H), 2.87-2.80 (m, 2H), 2.66-2.61 (in, 2H), 1.31-1.29 (m, 6H).
I 1 o ...._ v n .3 n r.) =
r.) ....
..r.:

c, Ge c, 4.-..

1-119 and I-HN
595-3 ill NMR (400 MHz, CD30D) 6 8.55-8.51 (m, 1H), 8.00-7.97 (m, 1H), 7.58-7.56 (m, 1H), 7.43-7.41 (m, 1H), 7.26-7.23 (m, 1H), 6.95-6.91 (in, 1H), ' .,=N 0 6.79-6.75 (m, 1H), 5.92-5.88 (m, 1H), 4.72-4.68 (m, 3H), 4.65-4.61 (m, 1H), "
o 4.58-4.54 (m, 1H), 4.48-4.43 (m, 1H), 4.06-4.00 (m, 1H), 3.98-3.94 (m, 2H), -.
nlis)1 3.83-3.78 (in, 111), 3.68 (s, 3H), 3.21-3.14 (m,111), 2.93-2.87 (m, 211), 2.85-a.
4.
..1 w 2.76 (m, 3H), 2.59-2.52 (m, 2H), 1.28-1.26 (tn, 3H).
en 145 I 597.3 1-118 and 1-0 ,.,N 1 Oliry.NS ill NMR (400 MHz, CD30D) 6 8.55-8.51 (m, 1H), 7.99-7.95 (m, 1H), 7.58-MN 7.56 (m, 1H), 7.43-7.40 (m, 1H), 7.25-7.22 (in, 1H), 6.95-6.91 (in, 1H), I '-µ 0 N ---14 6.79-6.75 (m, 1H), 5.92-5.88 (m, 1H), 4.59-4.53 (m, 1H), 4.50-4.42 (m, 1H), _E
,:!) 4.02-3.94 (m, 2H), 3.81-3.76 (m, 1H), 3.68 (s, 3H), 3.58-3.53 (m, 2H), 3.38-3.34 (in, 1H), 3.33 (s, 3H), 2.98-2.88 (in, 4H), 2.81-2.76 (m, 2H), 2.72-2.65 51 (m, 1H), 2.59-2. (m, 2H), 1.42-1.38 (m, 3H).

..
o .
\
I-.4 ...
(7,1 146 I
1124 and 1 .
...
tn o N 511.2 1H NMR (400 MHz, CD30D/CDC13=1/2) 6 8.63-8.61 (m, 1H), 8.60-8.57 - -.
I CN......\
(m, 1H), 7.97-7.91 (m, 1H), 7.71-7.67 (m, 1H), 7.60-7.56 (in, 1H), 7.30-7.25 129 .
.
.
FIN

.,.I. j4 I .2'N 0 (M, 111), 7.12-7.08 (in, 1H), 7.08-7.02 (m, 1H), 6.97-6.92 (m, 1H), 6.72-6.66 ..
.
.
, .
-.. I (m, 1H), 4.57-4.53 (m, 1H), 4.45-4.40 (in, 1H), 3.84 (s, 3H), 3.75 (s, 3H), .
2.96-2.89 (m, 2H), 2.86-2.80 (m, 2H), 2.64-2.56 (m, 2H).
0., 147 I ON 01-1 496.2 1H NMR (400 MHz, CD30D/CDC13=1/2) 6 8.99-8.95 (m, 1H), 8.59-8.55 1-104 and 1-7 r:SI
`,. N I (in, 1H), 7.93-7.89 (m, 111), 7.61-7.58 (In, 1H), 7.34-7.30 (m, 1H), 7.22-7,18 129 ..,... ----, N
I (m, 1H), 7.10-7.07 (m, 1H), 7.07-7.03 (m, 1H), 6.73-6.67 (m, 1H), 4.58-4.52 ,- 0 N 1 (m, 1H), 4.43-4.38 (m, 11-1), 3.77 (s, 3H), 2.95-2.90 (m, 211), 2.86-2.81 (m, v n ,N
wi 2H), 2.63-2.57 (m, 5H).
_______________________________________________________________________________ ___________________ n r.) =
r.) ....
..r.:
-a c, oe c, ,:.-.

_ 148 I ON õOH N
583.2 1-115 and 1-ic,(L9 I 'H NIVIR (400 MHz, CD30D) 8 8.58-8.54 (m, 11), 7.97-7.92 (m, 111), 7.60- 129 7.57 E (m, 1H), 7.50-7.46 (m, 1H), 7.23-7.19 (m, 1H), 7.00-6.95 (m, 111), 0 p \ ti 6.78-6.73 (m, 1H), 5.89-5.84 (m, 1H), 4.56-4.54 (m, 1H), 4.50-4.45 (m, 1H), k4 ,-.
J 4.09-4.03 (m, 2H), 3.76-3.73 (m, 2H), 3.71 (s, 3H), 3.63-3.59 (m, 2H), 3.37 N
,-.
ON
4.
..1 (s, 3H), 3.08-3.02 (m, 2H), 2.95-2.90 (m, 2H), 2.84-2.78 (m, 4H), 2.62-2.54 (m, 2H).
w en o \

566.0 1-36 and I-oN --Nõ Nii:
\ 'H NMR (400 MHz, CD30D/CDC13=3/1) 8 8.53 (d, J = 5.1 Hz, 1H), 8.45 (d, 129 H
I N',44 0 J = 2.2 Hz, 1H), 7.56-7.52 (m, 3H), 7.15 (d, J = 5.9 Hz, 1H), 6.99-6.86 (m, 1 3H), 6.71 (d, J = 5.9 Hz, 111), 4.57-4.45 (in, 2H), 4.37-4.28 (m, 1H), 4.09-4.07 (m, 2H), 3.73-3.60 (m, 5H), 3.31 (s, 3H), 2.90-2.88 (in, 2H), 2.80-2.78 N

w - Y (m, 2H), 2.57-2.55 (m, 2H).
.4"
I-I..
CA
CfN o.__.

n) .

153 I 528.2 IH NMR (400 MHz, CDC13) 8 8.53 (d, J = 5.0 Hz, 111), 7.97-7.95 (m, 1H), I-131 and I-i.) 0 N OHic :Si , 7.73-7.71 (In, 1H), 7.51-7.35 (in, 2H), 7.02 (s, 1H), 6.92 (d, J = 5.8 Hz, 1H), 129 FiN N

...
i.) I 6.63 (d, J = 5.9 Hz, 1H), 5.88 (s, 1H), 5.05 (d, J = 11.0 Hz, 1H), 4.50-4.38 ,,N 0 _ (11, 4H), 3.80-3.64 (m, 611), 3.32 (s, 3H), 2.92-2.72 (in, 4H), 2.62-2.47 (n, / o\ 2H).
154 556.3 I
IFI 1-131 and 1-4 ON OH NMR (400 MHz, CD30D) 8 8.53 (d, J = 5.1 Hz, 1H), 7.98 (d, .1 = 2.2 Hz, '' HN 1H), 7.56 (d, J = 5.1 Hz, 1H), 7.42 (d, J = 2.2 Hz, 1H), 7.21 (d, J = 5.9 Hz, mo I
n wk_. ,N 0 111), 6.92 (s, 1H), 6.77 (d, J = 5.9 Hz, 1H), 6.06 (s, 1H), 4.63-4.37 (m, 4H), /N o 3.74-3.66 (m, 6H), 3.31 (s, 3H), 2.80-2.53 (Tn. 4H), 1.30-1.26 (m, 6H). n \
r.) = _ r.) ....
..r.:

c, Ge c, 4.-..

0 OHI 526. 1 --1-132 and 1-c.r. Nis90 H NMR (400 MHz, CDC13) 8 8.53 (d, J = 5.1 Hz, 1H), 7.99 (d, J = 2.2 Hz, 1H), 7.73 (d, J = 2.2 Hz, 1H), 7.49-7.41 (in, 2H), 7.00 (s, 1H), 6.92 (d, J =

HN -N- N ----I 5.9 Hz, 1H), 6.63 (d, J =
5.9 Hz, 1H), 5.69 (s, 1H), 5.06 (d, J = 9.9 Hz, 1H), "
,N 0 p \ f 4.77 (s, 2H), 4.57-4.26 (m, 2H), 4.14-3.98 (m, 4H), 3.67 (s, 3H), 2.88-2.75 -.
N
I-.
a.
(m, 4H), 2.59-2.50 (m, 2H).
4.
ta 0 NI 555.0 1-132 and I-01-14,-..N \ 1H NMR (400 MHz, CD30D) 8 8.57-8.50 (m, 1H), 8.39(s, 1H), 8.01-7.92 114 r! , HN 1 "-- i (n, 1H), 7.59-7.54 (m, 111), 7.43-7.36 (m, 1H), 7.03 (s, 1H), 5.84 (s, 1H), ' ., N 0 Ers14 4.76-4.71 (In, 211), 4.59-4.48 (m, 2H), 4.09-4.04 (m, 2H), 4.01-3.94 (m, 2H), o--/ 3.67 (s, 3H), 2.85-2.79 (m, 2H), 2.66-2.60 (m, 2H), 1.30 (s, 6H).
159 1 595.0 ' 1-133 and 1-4 OH N, 0 N ___ ( .H NMR (400 MHz, CD30D) 8 8.80-8.78 (m, 1H), 8.52 (d, J = 5.1 Hz, 1H), ..
,., HN I
-1"
...N 0 7.65-7.49 (m, 2H), 7.32-7.12 (m, 2H), 6.96-6.64 (m, 3H), 4.65-4.29 (m, 4H), vs ...1,ii 4-' -.1 4.28-4.15 (in, 2H), 3.85-3.83 (m, 2H), 3.68 (s, 3H), 3.31 (s, 3H), 2.80-2.52 .
..
A (M, 4H), 1.29-1.25 (m, 6H).
.I.
Y

..-o, 162 0 4 0H .,õ 554.0 'H NMR (400 MHz, CD30D) 8 8.57-8.50(m, 1H), 8.05-7.97 (in, 1H), 7.62- 1-132 and 1-4 1 ICN\ 7.53 (m, 111), 7.44 (s, 1H), 7.26-7.16 (m, 1H), 6.92 (s, 1H), 6.82-6.73 (m, HN
111), 5.85 (s, 1H), 4.80-4.69 (in, 2H), 4.61-4.53 (m, 1H), 4.51-4.41 (m, 1H), o--) 4.10-4.05 (m, 2H), 4.03-3.93 (m, 2H), 3.68 (s, 3H), 2.77-2.70 (m, 2H), 2.63-2.58 (in, 2H), 1.29-1.25 (in. 6H).
mo i n n r.) =
r.) ....
..r.:
¨a c, oe c, :.-..

I 164 1 1 624.3 1 1-122 and I-0 N 0 1 H NMR (400 MHz, CD30D) 8 8.55-8.49 (m, 1H), 7.98-7.92 (in. 1H), 7.58--. 1 4 --.\

HN 1 .. 1 ' 7.54 (m, 1H), 7.42-7.37 (m, 1H), 7.06-7.01 (m, 1H), 5.89-5.82 (in, 1H), 0 ,N 0 t.) Etr, 4.74-4.70 (m, 2H), 4.64-4.59 (m, 2H), 4.56-4.49 (m, 2H), 4.05-3.98 (m, 2H), o b.) NJ 3.76-3.70 (m, 1H), 3.67 (s, 3H), 3.60-3.48 (m, 2H), 3.06-3.01 (m, 2H), 2.86- ,-.
-.
,-.
ON
4.
2.79 (in, 2H), 2.62-2.58 (m, 511), 1.30 (s, 6H).
..) c.) do cn 165 i 582.3 1-135 and 1-N 1H NMR (400 MHz, CD30D) 8 8.54-8.48 (in, 1H), 8.41-8.35 (m, 1H), 7.96-N *---H N' 7.92 (m, 1H), 7.57-7.53 (m, 1H), 7.40-7.36 (m, 1H), 7.06-6.99 (m, 1H), EN .. 5.88-5.83 (m, 1H), 4.58-4.48 (m, 2H), 4.04-3.99 (m, 2H), 3.65 (s, 3H), 3.64-N-) 3.62 (m, 2H), 2.95-2.91 (m, 2H), 2.84-2.79 (m, 2H), 2.63-2.57 (in, 4H), 1.29 (s, 6H), 1.17-1.13 (in, 3H).

169 540.2 IFINMR (400 MHz, CD30D/CDC13=1/1) 8 8.94-8.85 (m, 1H), 8.63-8.55 1-137 and 1-4 .
,., I-ON
0 , sl MEI 1 HtsrELIS:1-- (In, 1H), 7.84-7.78 (m, 1H), 7.66-7.61 (m, 1H), 7.34-7.28 (m, 1H), 7.13-7.08 ..
.
...
tn co HN if -s- --,,... N 11.........N 0 (m, 1H), 7.07-6.99 (m, 2H), 6.76-6.67 (m, 1H), 4.58-4.55 (in, 2H), 4.47-4.41 10 -. 14 (m, 1H), 4.05 (s, 3H), 3.77 (s, 3H), 2.80-2.72 (in, 2H), 2.70-2.62 (m, 2H), .
.

o., 1.33 (s, 611).
...
1-138 and 1-o 4 at 7rtii sy - 608.3 i H NMR (400 MHz, CD30D/CDC13=1/1) 8 8.62-8.56 (in, 1H), 8.26-8.21 NW (111, 1H), 7.94-7.90 (m, 1H), 7.58-7.56 (m, 1H), 7.49-7.45 (m, 1H), 7.14-7.09 I
,.. ..N 0 \ N7 i i (in, 1H), 5.87-5.83 (m, 1H),4.58-4.49 (m, 2H), 4.10-4.05 (m, 2H), 3.72 (s, 3H), 3.60-3.55 (in, 2H), 3.07-2.98 (m, 1H), 2.88-2.83 (m, 4H), 2.70-2.65 (m, NJ
d i i 2H), 2.20-2.12 (m, 2H), 2.01-1.90 (in, 2H), 1.84-1.72 (m, 2H), 1.34 (s, 6H). v n i-3 n r.) =
r.) ....
..r.:

c, Ge c, 4.-..

-1 _ 71 I -,/___. 594.3 1-139 and 1-O st:i 01-14p4;NISH 'H NMR (400 MHz, CD30D/CDC13=1/1) 8 8.62-8.55 (m, 111), 8.28-8.23 HN 1 (al, 1H), 7.93-7.88 (in, 1H), 7.58-7.55 (m, 1H), 7.48-7.45 (m, 1H), 7.14-7.09 o ,...N 0 k.) EN (DI, 1H), 5.87-5.82 (m, 1H), 4.57-4.52 (in, 2H), 4.08-4.03 (m, 2H), 3.86-3.82 =
b.) (n, 2H), 3.72 (s, 3H), 3.19-3.14 (m, 2H), 2.87-2.82 (m, 2H), 2.77-2.65 (m, -. ,-.
N-/
cN
'(: 2H), 1.98-1.90 (m, 1H), 1.34 (s, 6H), 0.64-0.57 (in, 2H), 0.56-0.51 (m, 2H). 4.
-.1 t.e vi 172 I - N OHSf 526.2 1H NMR (400 MHz, CD30D) 8 8.52-8.48 (m, 1H), 7.81-7.77 (m, 1H), 7.53-1-140 and 1-4 0 1 .
7.48 (m, 2H), 7.30-7.28 (m, 1H), 7.23-7.20 (m, 1H), 7.07-7.04 (m, 111), HN I .,õ 6.94-6.90 (m, 1H), 6.77-6.72 (in, 1H), 4.53-4.42 (m, 2H), 4.14-4.07 (m, 2H), N-N 3.67 (s, 3H), 2.77-2.68 (m, 2H), 2.65-2.56 (m, 2H), 1.43-1.38 (m, 3H), 1.29-1.26 (in, 6H).
173 I 540.2 'FINMR (400 MHz, CD30D) 8 8.53-8.49 (m, 1H), 7.84-7.81 (in, 1H), 7.54- 1-141 and 1-4 0 N 014243;

7.49 (m, 2H), 7.30-7.27 (m, 1H), 7.24-7.21 (in, 1H), 7.10-7.07 (m, 1H), .
I ..-N 0 6.94-6.90 (in, 1H), 6.77-6.73 (m, 1H), 4.53-4.45 (in, 2H), 4.45-4.40 (in, 1H), 1.-;
i..
,...
ei .
vs i..
VD

14}- N 3.68 (s, 3H), 2.76-2.70 (in, 2H), 2.63-2.59 (m, 2H), 1.46-1.43 (m, 6H), 1.29- "
--C 1.27 (m, 6H).
.
" i .
174 540.3 1-142 and 1-4 0 I-ON s .,11 oHN,r..i. isr6;11" 1H NMR (400 MHz, CD30D) 8 8.53-8.48 (m, 1H), 7.81-7.77 (m, 1H), 7.54-2.48 (in, 2H), 7.31-7.28 (m, 1H), 7.23-7.20 (m, 1H), 7.07-7.05 (m, 1H), ---' 0 6.94-6.90 (m, 1H), 6.76-6.73 (in, 1H), 4.53-4.42 (in, 2H), 4.05-4.00 (m, 2H), N-N 3.68 (s, 3H), 2.78-2.68 (m, 2H), 2.66-2.56 (m, 2H), 1.87-1.77 (m, 2H), 1.29-1.27 (in, 6H), 0.89-0.85 (in, 3H).
175 I 1 556.2 1-143 and 1-4 O ,...N OH
Hi (..N.97- 'H NMR (400 MHz, CD30D) 8 8.52-8.49 (m, 1H), 7.79-7.77 (m, 1H), 7.53- v n . 3 c, I , ,), lor-L
7.50 (m, 2H), 7.32-7.29 (m, 1H), 7.23-7.20 (m, 1H), 7.06-7.04 (m, 1H), n N-N 6.93-6.90 (m, 1H), 6.76-6.72 (m, 1H), 4.54-4.42 (m, 2H), 4.24-4.20 (in, 2H), N.) =
oS 3.71-3.67 (m, 5H), 2.78-2.68 (m, 2H), 2.65-2.57 (m, 2H), 1.29-1.27 (in, 6H). N.) --..r-=
-.) \
c, Ge c, 4.-..

189 I 580.2 ill NMR (400 MHz, CDC13) 6 8.67 (d, J = 2.1 Hz, 1H), 8.56 (d, J ¨ 5.0 Hz, 1-147 and I-ON
1H), 7.93 (t, J = 2.4 Hz, 1H), 7.89-7.78 (m, 2H), 7.51-7.47 (m, 1H), 7.29-1 ....hi 0 \ 1 j 7.25 (m, 1H), 7.03 (s, 1H), 6.93 (d, J = 5.9 Hz, 1H), 6.81 (d, J = 8.9 Hz, 1H), 6.64 (d, J = 5.9 Hz, 1H), 5.09 (d, J = 11.5 Hz, 1H), 4.56-4.27 (m, 2H), 3.93-)4 o b.) ,-.
, ,-.
3.69 (m, 6H), 3.59-3.52 (m, 1H), 3.42-3.40 (m, 1H), 3.07-2.95 (m, 2H), o 4.
..310..) 2.85-2.81 (m, 4H), 2.63-2.47 (m, 2H), 0.96-0.94 (m, 3H).
w en --- .., 191 678.4 1-112 and I-o 4 , 1 N \ 1H NMR (400 MHz, CD30D/CDC13=1/1) 8 8.67-8.61 (m, 1H), 8.58-8.54 114 N ---HN., I (n, 1H), 8.22-8.17 (m, 1H), 8.03-7.99 (m, 1H), 7.57-7.54 (m, 2H), 7.42-7.39 ,..., isj j N 0 I (in, 1H), 7.09-7.05 (m, 1H), 6.91-6.86 (m, 1H), 4.70-4.64 (m, 3H), 4.56-4.48 (m, 3H), 3.69 (s, 3H), 3.50-3.43 (m, 1H), 3.20-3.03 (m, 2H), 2.82-2.77 (m, ......N) 211), 2.64-2.60 (m, 2H), 2.46-2.37 (m, 2H), 2.21-2.15 (m, 2H), 1.29 (s, 6H), N

<I 1.04 (s, 6H).
..
,., ..,"
Ial "
4 - 514.2 1 El NMR (400 MHz, CD30D/CDC13=1/1) 8 8.56-8.54 (m, 1H), 8.22-8.18 1-106 and 1- ..
I-I-0 o 0 01 192 -114;NSL
_. I
0"
N --- (m, 11-1), 8.08-8.06 (m, 111), 7.64-7.62 (m, 111), 7.56-7.54 (m, 111), 7.08-7.05 114 i.) i.) HN \
=
1 N 0 (m, 1H), 5.95-5.92 (m, 1H), 4.52-4.46 (m, 2H), 3.69 (s, 3H), 2.81-2.78 (m, .0 , W'r1 --ig 0' 1 2H), 2.63-2.61 (m, 2H), 2.33 (s, 3H), 1.29 (s, 6H).
193 ON HN N 678.3 'H NMR (400 MHz, CDC13) 8 8.72-8.67 (m, 1H), 8.64-8.60 (m, 1H), 8.04- 1-149 and I-. 1 tti \ 8.01 (m, 1H), 8.00-7.96 (m, 1H), 7.89-7.85 (m, 1H), 7.72-7.69 (m, 1H), 114 I '.
,..Ø41 o 7.51-7.49 (m, 1H), 7.38-7.33 (m, 1H), 7.12-7.09 (m, 1H), 6.83-6.78 (m, 1H), . 4.77-4.70 (m, 2H), 4.66-4.58 (m, 2H), 4.54-4.41 (m, 2H), 3.79-3.69 (m, 4H), e) (R..µ,. 3.24-3.12 (m, 1H), 2.94-2.86 (m, 1H), 2.78-2.76 (m, 2H), 2.75-2.66 (m, 2H), mo n N 2.66-2.63 (m, 2H), 2.52-2.45 (m, 1H), 1.97-1.94 (m, 1H), 1.31 (s, 6H), 0.91- n <I 0.87 (m, 6H).

r.) c) =
r.) ....
..r.:
¨a c, oe c, :.-..

1-150 and 1-T),63(1111;
610.3 1 'H NMR (400 MHz, CD30D/CDC13=1/1) 8 8.74-8.65 (m, 1H), 8.61-8.52 I

N. I (m, 11-1), 8.27-8.15 (m, 311), 7.63-7.58 (m, 1H), 7.54-7.51 (m, 1H), 7.10-7.03 o 1 ,N 0 b.) NN i OM 111), 4.53-4.48 (m, 2H), 3.91-3.82 (m, 2H), 3.78-3.73 (m, 1H), 3.70 (s, =
y .
,-.
3H), 3.59-3.54 (m, 11-1), 3.51-3.45 (m, 1H), 3.11-3.01 (m, 2H), 2.83-2.77 (m, , ,-.
ct, pe)o) 2H), 2.66-2.59 (in, 211), 1.29 (s, 6H), 1.02-0.96 (in, 3H). .1.

W
Vs 0 NI 609.3 'FINMR (400 MHz, CD30D/CDC13=1/1) 8 8.59-8.57 (m, 1H), 8.57-8.54 1-147 and I-%
., (m, 1H), 8.21-8.17 (m, 1H), 7.92-7.88 (m, 1H), 7.56-7.53 (m, 1H), 7.53-7.51 114 HN I
-NO i (ii, 111), 7.35-7.31 (m, 111), 7.08-7.05 (m, 111), 6.95-6.91 (m, 111), 4.53-4.45 :
i I (m, 2H), 3.90-3.82 (in, 2H), 3.78-3.72 (m, 1H), 3.69 (s, 3H), 3.57-3.52 (m, 1 I H), 3.47-3.40 (m, 1H), 3.08-2.95 (in, 2H), 2.87-2.71 (m, 2H), 2.68-2.55 (in, ri 0 2H), 1.29 (s, 6H), 0.95-0.92 (m, 3H).

197 I -0 _ i 665.3 ; 0 0 N 1-., I II-I
1-151 and 1-NMR (400 MHz, CD3OD/CDC13=1/1) 8 8.72-8.68 (m, 1H), 8.59-8.55 ,., 114 i-..1 I--'NJ --I-C' wi HI I '' 'is 1 (in, 11-1), 8.25-8.23 (m, 21-1), 8.22-8.19 (m, 111), 7.63-7.60 (m, 1H), 7.55-7.52 '-' N' N 'N ro y (m, 1H), 7.09-7.05 (in, 1H), 4.72-4.68 (m, 2H), 4.66-4.64 (m, 1H), 4.60-4.56 (in, 1H), 4.54-4.47 (m, 2H), 3.70 (s, 3H), 3.55-3.48 (in, 2H), 3.15-3.05 (m, , i , ,-2H), 2.83-2.76 (m, 2H), 2.65-2.60 (m, 2H), 2.57-2.52 (n, 1H), 2.51-2.43 (m, "
N
6 2H), 2.24-2.18 (m, 1H), 1.29 (s, 6H), 1.03-0.99 (in, 311).

1-152 and 1-4 649.3 Nc:S
1H NMR (400 MHz, CD30D): 8 8.94 (d, J = 2.3 Hz, III), 8.56 (d, J = 5.1 Hz, 114), 7.71 (d, J = 2.3 Hz, 1H), 7.63 (d, J = 5.1 Hz, 1H), 7.49 (d, J = 9.3 IV
Hz, 1H), 7.42 (d, J = 9.2 Hz, 1H), 7.22 (dd, J = 5.9, 0.6 Hz, 1H), 6.93 (s, A
i-i 1H), 6.78 (d, J - 5.9 Hz, 1H), 4.71-4.46 (m, 6H), 3.72 (s, 3H), 3.58-3.49 (m, A

1H), 2.94-2.82 (m, 3H), 2.79-2.69 (m, 2H), 2.66-2.58 (n, 2H), 2.05-1.81 (m, t.) =
<1> 6H), 1.29 (d, J = 5.4 Hz, 6H).
-.
c:

CIN
GC
CIN
...7., 201 I 678.2 i 1-153 and 1-4 a N,N otiN26:21¨ i I H NMR (400 MHz, CDC13) 8 8.64-8.60 (m, 2H), 8.25 (s, 1H), 8.09 (d, .1 =

HN I 2.6 Hz, 1H), 7.55 (d, J = 5.0 Hz, 1H), 7.39-7.35 (m, 1H), 7.02-6.91 (in, 2H), 0 ,N 0 b.) =-=ti./ 0 I 6.87 (d, J = 5.9 Hz, 1H), 6.65 (d, J = 5.9 Hz, 1H), 4.76-4.54 (m, 5H), 4.50- b.) ,-.
-.
4.46 (m, 2H), 3.90 (s, 3H), 3.77-3.75 (m, 1H), 3.32-3.30 (m, 1H), 3.00-2.98 ON
4.
s);..... (n, 1H), 2.80-2.53 (m, 7H), 2.02-2.00 (m, 1H), 1.30-1.26 (m, 6H), 0.95-0.89 w N
Vs (m, 6H).

( 677.2 tH NMR (400 MHz, CD30D) 8 8.67-8.65 (m, 1H), 8.57-8.55 (m, 1H), 7.96- 1-154 and 1-4 1 oHNr... ,..N......\
7.95 (in, 1H), 7.63-7.59 (m, 1H), 7.59-7.55 (m, 111), 7.49-7.42 (m, 1H), ..-:14 0 7.26-7.20 (m, 1H), 7.07-7.00 (m, 1H), 6.94 (s, 1H), 6.82-6.76 (m, 1H), 4.72-4.68 (m, 2H), 4.65-4.58 (m, 4H), 4.20-4.14 (in, 2H), 3.52-3.47 (m, 2H), t) 3.13-3.02 (m, 2H), 2.80-2.69 (m, 2H), 2.66-2.61 (m, 2H), 2.60-2.54 (m, 1H), 2.51-2.45 (m, 2H), 2.22-2.18 (in, 1H), 1.44-1.40 (m, 3H), 1.28-1.27 (m, 6H), ,., .
.."
c, 6 0.98-0.96 (m, 3H).
w o 205 5 L 678.2 'H NMR (400 MHz CD3 OD/CDC13- =1/1) 68.78 0 = (d J = 2 2 Hz, 11-15 ) 8.54 1-155 and 1-4 NI' 0 NI c =0 CO
I
RN N. 1 , ...,... Ny--- (d, J = 5.1 Hz, 1H), 7.67 (d, J = 2.2 Hz, 1H), 7.60 (dd, J = 5.1, 3.3 Hz, 1H), z -N 0 7.19 (q, J = 9.7 Hz, 2H), 7.11 (d, J = 6.0 Hz, 1H), 6.95 (s, 1H), 6.69 (d, J =
N.... N 5.9 Hz, 1H), 4.69-4.41 (m, 6H), 4.33-4.23 (m, 1H), 3.93-3.83 (m, 1H), 3.76-3.63 (m, 4H), 3.44-3.34 (in, 1H), 3.06-2.95 (m, 1H), 2.91-2.81 (m, 1H), (s)(R
N 2.78-2.65 (m, 2H), 2.64-2.55 (m, 2H), 2.41-2.28 (in, 1H), 1.30-1.22 (m, 9H), 6 0.98-0.89 (m, 3H).
a v n .3 n r.) =
r.) ....
..r.:

c, Ge c, 4.-..

206 666.3 1-156 and 1-ON i \ 1 N =-= \ -1H NMR (400 MHz, CDC13) 8 8.74-8.55 (m, 2H), 8.02-7.90 (m, 211), 7.84-.,,,.. Nil ,-N 0 7.77 (m, 11-1), 7.72-7.64 (m, 1H), 7.55-7.46 (m, 1H), 7.33-7.27 (m, 1H), k4 o i b.) .. 7.14-7.04 (m, 1H), 6.82-6.75 (m, 1H), 4.59-4.33 (m, 311), 3.70 (s, 311), 3.56- ,-.
....
I-.
cr.
's) ) 3.49 (m, 2H), 3.44-3.38 (m, 1H), 3.36 (s, 3H), 3.1-2.99 (m, 211), 2.80-2.70 4.
-.1 W
N (m, 3H), 2.67-2.55 (m, 61-), 2.36-2.28 (in, 1H), 1.31 (s, 6H), 0.95 (s, 3H). en Li 1 and 1-680.4 111 NMR (400 MHz, CDC13) 68.77-8.66 (m, 1H), 8.66-8.57 (in, 1N), 8.06--157 a ',fõr,;141 8.01 (m, 11-1), 8.01-7.94 (m, 1H), 7.90-7.81 (m, 1H), 7.76-7.66 (m, 111), HN 1 .;µ, n , .. .* i .... .. ..z......., . . . . 7.56-7.46 (m, 1H), 7.40-7.33 (m, 1H), 7.14-7.06 (m, 1H), 6.82-6.75 (in, 1H), . 4.60-4.34 (m, 3H), 3.70 (s, 3H), 3.59-3.46 (m, 2H), 3.35 (s, 31-1), 3.16-3.07 ra..4. (s, 1H), 3.06-2.95 (m, 2H), 2.94-2.87 (m, 114), 2.82-2.66 (m, 3H), 2.66-2.53 .
,., N (m, 3H), 2.49-2.43 (m, 1H), 2.24-2.17 (m, 1H), 1.30 (s, 6H), 1.08-1.00 (m, ...1 .
.."
ch L) w ...
" 3H), 0.90-0.83 (m, 3H).
.
0., .
208 r--11 538.2 III NMR (400 MHz, CDC13) 8 8.72-8.68 (m, 1H), 8.41-8.37 (m, 1H), 8.37- 1-21 and 1- .I.
N N ONSL

k, llsc =
8.33 (m, 1H), 8.04-8.00 (m, 2H), 7.81-7.77 (m, 1H), 7.73-7.71 (in, 1H), 7.54-7.52 (m, 1H), 7.17-7.13 (m, 1H), 4.75-4.70 (m, 1H), 4.57-4.49 (m, 2H), elsr4 ' ..-N 0 N-N 4.44-4.38 (m, 2H), 2.81-2.78 (m, 2H), 2.68-2.65 (in, 21-1), 1.61-1.56 (m, 3H), C 1.33 (s, 6H).
v n .3 n t4 =
N
....

GC
...7., 209 1 I 0 :i 679-3 tH NMR (400 MHz, CDC13) 8 8.76-8.72 (m, 1H), 8.62-8.59 (m, 1H), 8.02- 1 114-155 and I-, 1 01-1171,,rSj 7.97 (m, 1H), 7.78-7.75 (m, 1H), 7.75-7.73 (in, 1H), 7.55-7.52 (m, 1H), N 0 7.12-7.08 (m, 1H), 6.99-6.94 (m, 2H), 4.69-4.66 (m, 2H), 4.65-4.60 (m, 2H), "
o b.) Lt _N 4.53-4.37 (m, 3H), 4.33-4.29 (m, 1H), 3.91-3.84 (m, 1H), 3.80-3.75 (m, 1H), -.
,-.
cr.
)(;,,, 3.73 (s, 3H), 3.44-3.38 (m, 1H), 3.06-2.99 (m, 1H), 2.91-2.85 (m, 1H), 2.81- 4.

4a N 2.74 (m, 2H), 2.67-2.61 (in, 2H), 2.36-2.32 (m, 1H), 1.32 (s, 6H), 1.25 (s, en 3H), 0.94-0.92 (in, 3H).
210 r J. 692.3 tH NMR (400 MHz, CDC13) 8 8.70-8.66 (in, 1H), 8.65-8.60 (m, 1H), 8.05- 1-158 and I-8,01 (in, 1H), 8.00-7.96 (m, 1H), 7.90-7.86 (m, 111), 7.77-7.74 (m, 1H), HN I N 7.54-7.50 (m, 1H), 7.37-7.33 (m, 1H), 7.12-7.08 (m, 1H), 6.82-6.77 (m, 1H), ..-...., , ---i 4.77-4.68 (m, 2H), 4.66-4.58 (m, 2H), 4.56-4.40 (in, 3H), 4.21-4.11 (m, 2H), R1 3.79-3.69 (m, 1H), 3.23-3.12 (m, 1H), 2.94-2.87 (m, 1H), 2.80-2.76 (m, 2H), 0 N 2.76-2.67 (m, 2H), 2.66-2.62 (m, 2H), 2.52-2.41 (m, 1H), 1.98-1.91 (m, 1H), ,...

a. 6 1.46-1.41 (m, 3H), 1.31 (s, 6H), 0.91-0.86 (m, 6H).
4. 0 to 211 r 678.4 1-154 and I-17ry. 'H NMR (400 MHz,CDC13) 8 8.68-8.64(m, 1H), 8.64-8.59 (m, 1H), 8.01- 114 i . 1 4 -\,..-HN I 7.93 (in, 2H), 7.86-7.81 (m, 1H), 7.76-7.72 (m, 1H), 7.54-7.50 (m, 1H), ..,.7 ...N 0 i 7.32-7.28 (m, 1H), 7.13-7.07 (m, 1H), 6.82-6.77 (m, 1H), 4.72-4.59 (m, 4H), -..
4.55-4.38 (m, 3H), 4.20-4.11 (m, 2H), 3.57-3.38 (m, 2H), 3.11-3.01 (m, 2H), t ) 2.81-2.72 (m, 2H), 2.68-2.60 (m, 2H), 2.58-2.51 (m, 1H), 2.49-2.40 (m, 2H), N
6 2.23-2.16 (m, 1H), 1.47-1.40 (m, 3H), 1.31 (s, 6H), 1.00-0.96 (m, 3H).
o mig n n t4 =
N
1-.

GC
..^.:

212 0 4 _ 610.3 i i ill NMR (400 MHz, CDC13) 8 8.76-8.72 (in, 1H), 8.63-8.58 (m, 1H), 8.01-1-159 and 1-E... 0 i 7.96 (m, 1H), 7.81-7.74 (m, 2H), 7.56-7.50 (m, 1H), 7.12-7.08 (in, 1H), o N I 7.01-6.92 (m, 2H), 4.56-4.36 (m, 2H), 4.16-4.09 (m, 1H), 4.05-3.97 (m, 1H), =
b.) ,-.
3.84-3.76 (m, 3H), 3.72 (s, 3H), 3.67-3.60 (m, 1H), 3.37-3.25 (m, 11 1), 2.81--.
,-.
a, ,, s'oN) 2.73 (m, 2H), 2.67-2.61 (m, 2H), 1.31 (s, 6H), 1.25-1.22 (m, 3H). 4.
-.1 ta en 213 c) 4 665.3 1-160 and 1-1H NMR (400 MHz, CDC13) 8 8.77-8.72 (m, 1H), 8.62-8.58 (m, 1H), 8.00-, \

NW,I 4; 7.96 (m, 1H), 7.82-7.70 (m, 2H), 7.55-7.51 (in, 1H), 7.11-7.07 (m, 1H), 6.98-6.95 (in, 2H), 4.70-4.64 (m, 3H), 4.61-4.57 (m, 1H), 4.54-4.36 (m, 2H), 4.34-4.28 (m, 1H), 4.02-3.93 (m, 1H), 3.72 (s, 3H), 3.51-3.44 (m, 1H), 3.32-ts) ) 3.30 (in, 1H), 2.82-2.75 (m, 3H), 2.66-2.62 (in, 2H), 2.62-2.57 (m, 1H), N
6 2.27-2.22 (m, 1H), 2.08-1.97 (m, 2H), 1.31 (s, 6H), 1.28-1.25 (m, 3H). 0 ,., c) I-.4 ." 114 r 623.2 1H NMR (400 MHz, CD30D/CDC13=1/1) 8 8.81-8.74 (m, 1H), 8.57-8.50 1-161 and 1-4 ...

I-ON
ei.
i.) tn ,,1 (m, 1H), 7.76-7.69 (in, 1H), 7.64-7.59 (m, 1H), 7.27-7.21 (m, 1H), 7.19-7.13 " 0 ,9 HN I (in, 1H), 7.14-7.09 (m, 1H), 6.95 (s, 1H), 6.73-6.66 (m, 1H), 4.57-4.48 (m, i.) .I.

=
-... N 1H), 4.44-4.39 (m, 1H), 4.23-4.10 (m, 3H), 4.02-3.96 (m, 1H), 3.84-3.74 (m, 4-' 211), 3.74-3.68 (m, 1H), 3.66-3.59 (m, 1H), 3.29-3.22 (m, 1H), 2.78-2.66 (in, .3)o) 2H), 2.66-2.55 (m, 2H), 1.46-1.39 (m, 3H), 1.30-1.25 (m, 6H), 1.22-1.18 (m, 3H).
v n .3 n r.) =
r.) ....
..r.:

c, Ge c, 4.-..

I 215 r j___ 691.4 0 N 011NS 1 i 1-158 and 1-4 I 'H NMR (400 MHz, CD3OD) ö 8.75-8.69 (in, 1H), 8.58-8.53 (m, 1H), 8.03-4..-... , 7.97 (in, 1H), 7.62-7.58 (m, 2H), 7.51-7.47 (m, 111), 7.24-7.19 (m, 1H), ,.... .pjj ....N 0 1 : 7.06-7.00 (m, 1H), 6.93 (s, 1H), 6.81-6.75 (m, 1H), 4.75-4.71 (m, 1H), 4.69- b.) 0 b.) . i 4.65 (m, 2H), 4.64-4.57 (m, 2H), 4.50-4.46 (in, 1H), 4.20-4.12 (m, 2H), -...
,-.
:
c), i 3.81-3.73(m, 1H), 3.24-3.16 (m, 11-1), 2.94-2.88 ( nl, 1H), 2.78-2.69 (m, 4H), 4.
-.1 N 1 2.66-2.58 (m, 2H), 2.54-2.46 (m, 1H), 2.00-1.88 (m, I H), 1.44-1.39 (m, 3H), en 1.30-1.27 (m, 6H), 0.90-0.86 (m, 6H).
o 1-163 and 1-oc...:j3 680.4 1H NMR (400 MHz, CDC13) 8 8.69-8.64 (m, 1H), 8.64-8.60 (m, 1H), 8.01-. I 4 \

HN i `,..,N 0 7.97 (m, 1H), 7.97-7.94 (m, 1H), 7.83-7.77 (m, 1F1), 7.72-7.67 (m, 1H), 7.55-7.48 (m, 1H), 7.32-7.28 (m, 1H), 7.12-7.08 (m, 1H), 6.82-6.77 (m, 1H), . 4.63-4.33 (m, 3H), 3.71 (s, 3H), 3.52-3.46 (m, 1H), 3.45-3.38 (m, 1H), 3.35 D (s, 3H), 3.33-3.28 (in, 1H), 3.07-3.00 (m, 2H), 2.85-2.75 (m, 4H), 2.75-2.60 .
,., ...
N (n, 4E1), 2.47-2.42 (m, 111), 1.31 (s, 6H), 1.08-1.03 (m, 3H), 0.98-0.92 (m, ..1 I..
1.., I-C,'C1 *
.
NI).
"
O,_.
.
.
, .
220 1 680.4 I-' ' 1-164 and I-H NMR (400 MHz, CDC13) 6 8.73-8.67 (m, 1H), 8.66-8.60 (m, 1H), 8.06-114 ..
i4N-'-'-"'"Ci- 8.02 (m, 1H), 8.00-7.96 (m, 1H), 7.88-7.84 (m, 1H), 7.73-7.69 (in, 1H), LN ' .i) 7.53-7.50 (m, 1H), 7.37-7.33 (m, 1H), 7.12-7.08 (m, 1H), 6.77-6.73 (m, 1H), C
.....\,.N,, -..N.) 4.57-4.36 (in, 3H), 3.71 (s, 3H), 3.54-3.50 (m, 2H), 3.36 (s, 3H), 3.20-3.00 (m, 2H), 2.81-2.73 (m, 2H), 2.68-2.61 (m, 2H), 2.60-2.53 (m, 4H), 2.39-2.32 (m, 2H), 1.31 (s, 6H), 1.03 (s, 6H).
...._ n .3 n t4 =
N
....

::"
GC
::"
..I., _ 1-110 and I-0 !II
678.4 01-11;621--- iH NMR (400 MHz, CDC13) 8 8.69-8.58 (m, 211). 8.01-7.95 (m, 1H), 7.94-, I N

HN 7.88 (m, 111), 7.82-7.75 (m, 111), 7.69-7.66 (m, 1H), 7.52-7.49 (m, 1H), 0 7.14-7.07 (m, 1H), 6.84-6.75 (m, 1H), 4.71-4.58 (in, 4H), 4.57-4.35 (m, 3H), 3.71 (s, 3H), 3.54-3.46 (m, 1H), 3.32 (s, 1H), 3.16-3.07 (in, 2H), 2.81-2.74 (in, 211), 2.68-2.61 (m, 211), 2.59-2.52 (m, 111), 2.47-2.37 (m, 2H), 2.36-2.27 ON
(m, 1H), 1.44-1.34 (in, 2H), 1.31 (s, 6H), 0.85-0.77 (m, 3H).
Jl 226 Irffy- 679.4 1-164 and 1-4 1.4 IHNMR (400 MHz, CD30D) 8 8.73 (d, J 2.1 Hz, 1H), 8.55 (d, J = 5.1 Hz, 1H), 8.01 (d, J = 2.5 Hz, 1H), 7.59 (d, J = 5.1 Hz, 1H), 7.54 (d, J = 2.2 Hz, 1H), 7.48-7.46 (m, 1H), 7.22 (d, J = 5.9 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H), 6.93 (s, 1H), 6.78 (d, J = 5.9 Hz, 1H), 4.59-4.46 (m, 2H), 3.70 (s, 311), 3.57-3.51 (in, 2H), 3.34 (s, 3H), 3.13-3.09 (m, 2H), 2.74-2.70 (in, 2H), 2.64-2.51 (m, 6H), 2.41-2.39 (m, 2H), 1.30-1.26 (in, 6H), 1.05-1.01 (m, 6H).

1'0 r.) r.) Compound 2 2-(5-054(25,5R)-2,5-dimethy1-4-(oxetan-3-yl)piperazin-l-yl)pyridin-2-yl)amino)-3'-(hydroxymethyl)-1-methyl-6-oxo-1,6-dihydro-[3,4'-bispyridin1-2'-y1)-7,8-dihydro-2H-cyclopenta[4,51pyrrolo[1,2-alpyrazin-1(611)-one /--- N .)t, .
r.õ...... (NJ ,C>r ' 1 N= Step I
C . ..1., , N J--:..--.7 + reilvN......,..5e N ."F
I 'µr Y
:.. ., N 0 Nid HO-ELOH
0¨I

I I
0 NõOH
HN" ''' OTV-0 \ rsis:19 , ' Sy I I I
.õ.. N ..,4õ.....N _ -CN ..,-,N 0 .-u Step 2 ,õ.. -.....) ,,., N..s., . ) 1 tlµR) csip. N

Step 1: 5-05-025,5R)-2,5-dimethy1-4-(oxetan-3-yl)piperazin-l-yl)pyridin-2-yl)amino)-1-methyl-6-oxo-2'-(1-oxo-1,6,7,8-tetrahydro-2H-cyclopenta[4,51pyrrolo[1,2-a]pyrazin-2-y1)-1,6-dihydro43,4'-bispyridinF3'-carbaldehyde Under nitrogen, to a solution of (545-02S,5R)-2,5-dimethy1-4-(oxetan-3-yppiperazin-1-yl)pyridin-2-yl)amino)-1-methy1-6-oxo-1,6-dihydropyridin-3-yl)boracic acid (171 mg, 0.41 mmol) and 4-chloro-2-(1-oxo-1,6,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-c]pyrazin-2-yDnicotinaldehyde (100 mg, 0.32 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was added Xphos (20 mg, 0.03 mmol), Pd(dppf)C12 CH2C12 (25 mg, 0.03 mmol) and cesium carbonate (260 mg, 0.8 mmol).
The mixture was reacted at 90 C for 4 hours, and then cooled to room temperature. Water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL x 2). The organic phase was collected and combined, and concentrated in vacuum under reduced pressure to give the target product (180 mg, yield 68%), which was directly used in the next step. [M+H]+ 647.3 Step 2: 2-(54(54(25,5R)-2,5-dimethy1-4-(oxetan-3-yl)piperazin-l-yl)pytidin-2-yl)amino)-3 -(hydroxymethyl)-1-methy1-6-oxo-1,6-dihydro-[3,4'-bispyridin1-2s-y1)-7,8-dihydro-2H-eyclopenta[4,5]pyrrolo[1,2-alpyrazin-1(611)-one At 0-5 C, under nitrogen, to a solution of 54(54(25,5R)-2,5-dimethy1-4-(oxetan-3-yppiperazin-1-yppyridin-2-yDamino)-1-methyl-6-oxo-2'-(1-oxo-1,6,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-cdpyrazin-2-y1)-1,6-dihydro-[3,4'-bispyridin]-3'-carbaldehyde (180 mg, 0.28 mmol) in methanol (4 mL) and dichloromethane (10 mL) was added sodium borohydride (16 mg, 0.42 mmol), and reacted at room temperature for 15 minutes. The reaction was quenched by adding water (0.5 mL) to the reaction solution, and concentrated in vacuum under reduced pressure, and the resulting residue was purified with silica gel column chromatography (methanol/water) and purified with thin layer chromatography (methanol/dichloromethane =1/20) to give the target product (80 mg, yield 44%). [M+H] 649.3. 111 NMR (400 MHz, CD30D): 8 8.73 (d, J = 2.2 Hz, 1H), 8.54 (d, J = 5.1 Hz, 1H), 8.00 (d, J = 2.6 Hz, 1H), 7.59-7.46 (m, 3H), 7.24 (d, J = 5.9 Hz, 1H), 7.03 (d, J = 8.8 Hz, 1H), 6.94 (s, 1H), 6.79 (d, J = 5.9 Hz, 1H), 4.77-4.55 (m, 5H), 4.49-4.47 (m, 1H), 3.81-3.64 (m, 4H), 3.20-3.18 (m, 1H), 2.91-2.87 (m, 3H), 2.77-2.73 (m, 4H), 2.62-2.42 (m, 3H), 1.94-1.92 (m, 1H), 0.89-0.86 (m, 6H).
The compounds in the following table were prepared with corresponding intermediates and reagents according to the preparation steps of compound 2:

LC-MS
Compound Structural formula I HNMR
Intermediate (M+Hr b.) o b.) 12 1 647.3 Ili NMR (400 MHz, CD30D): 8 8.62-8.54 (m, 11-1), 8.44-8.37 1-54 and 1-77 .,-1-a\
===- II r (m, 1H), 7.99-7.90 (m, 1H), 7.46-7.33 (m, 2H), 7.21-7.14 (m, 4.
..1 HN---"---)1='== N'ir&L
ta 1H), 7.13-7.05 (m, 1H), 6.98-6.88 (m, 2H), 6.69-6.61 (m, 1H), v.
4.73-4.68 (m, 2H), 4.66-4.58 (m, 2H), 3.70 (s, 3H), 3.55-3.39 (m, y2H), 3.11-3.00 (m, 2H), 2.76-2.67 (m, 2H), 2.62-2.54 (m, 3H), t) ) 2.51-2.42 (m, 2H), 2.23 (s, 3H), 2.20-2.15 (m, 1H), 1.29-1.26 (m, N 6H), 0.98-0.93 (m, 3H).

..5;
38 D 667.4 'H NMR (400 MHz, CD30D): 8 8.67 (d, J = 2.3 Hz, 1H), 8.52 (d, 1-78 and 1-55, . .
DtD
1:1 lai --1 J = 5.1 Hz, 1H), 7.93 (d, J = 2.7 Hz, 1H), 7.56 (d, J = 5.1 Hz, 1H), 7.53-7.48 (m, 1H), 7.41 (dd, J = 8.9, 2.8 Hz, 1H), 7.20 (d, J
.
o 0 N i 0 a Acr.N.S1¨ NaBDI
:i = 5.9 Hz, 1H), 7.01 (d, J = 8.9 Hz, 1H), 6.92 (s, 1H), 6.77 (d, J =
:

.- N 0 7'N 1 5.9 Hz, 1H), 4.72-4.44 (m, 5H), 3.54-3.42 (m, 2H), 3.12 -2.95 ..
..,,r) (m, 2H), 2.77-2.66 (m, 2H), 2.65-2.58 (m, 2H), 2.57-2.51 (m, .) ) 1H), 2.49-2.39 (m, 2H), 2.23-2.14 (m, 1H), 1.27 (d, J = 6.2 Hz, N 6H), 0.95 (d, J = 6.3 Hz, 3H).

v n i-3 n r.) =
r.) ....
..r.:

c, oe c, t.-:

3'-) o 666.3 'NMR (400 MHz, CD30D): 6 8.68 (d, J = 2.1 Hz, 1H), 8.55 (d, 1-78 and 1-55 il..1 o FI
J = 5.0 Hz, 1H), 7.95 (d, J = 2.7 Hz, 1H), 7.59 (d, J = 5.2 Hz, lo.., ...r ,.OH icsrrii3 1H), 7.52 (d, J = 2.3 Hz, 1H), 7.44 (dd, J = 8.9, 2.8 Hz, 1H), 7.22 b.) FIN ''''''-'-ry=N ----(d, J = 5.9 Hz, 1H), 7.03 (d, J = 8.9 Hz, 1H), 6.93 (s, 1H), 6.78 o b.) .
--'51"N -=,,,-, N
0 -.
.
(d, J = 5.9 Hz, 1H), 4.72-4.47 (m, 6H), 3.56-3.44 (in, 2H), 3.14-o 4.
.)) ...i 3.01 (m, 2H), 2.79-2.69 (m, 2H), 2.66-2.59 (m, 2H), 2.59-2.54 w vi (m, 1H), 2.50-2.43 (m, 2H), 2.26-2.14 (m, 1H), 1.29 (d, J = 6.4 N Hz, 6H), 0.97 (d, J =
6.3 Hz, 3H).
o 52 F 663.3 'FINMR (400 MHz, CD3OD ): 6 8.68 (d, J = 2.0 Hz, 1H), 8.59 1-52 and 1-54 I _ 0..,.N..r õ..01-1(-,,..N \ / (d, J = 5.1 Hz, 1H), 7.96 (d, J = 2.5 Hz, 1H), 7.89 (d, J = 6.0 Hz, 0 FIN "--"-------.1 Is' ----.7.1..N ' ..N 0 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.62 (d, J = 5.1 Hz, 1H), 7.56-7.52 5..
;
.
;.' ¨
(m, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.48-7.42 (m, 1H), 7.34-7.25 .?.
-=1 ,...r. ) ro mr (n, 1H), 7.24-7.16 (m, 1H), 7.06-7.00 (in, 1H), 6.93-6.88 (in, li 1H), 4.73-4.58 (m, 6H), 3.70 (s, 3H), 3.56-3.45 (m, 2H), 3.16-.

N 3.02 (m, 2H), 2.62-2.55 (m, 1H), 2.52-2.45 (m, 2H), 2.26-2.16 ...
6 (m, 1H), 1.01-0.95 (m, 3H).
o 53 i 663.3 '11 NMR (400 MHz, CD30D): 6 8.68 (d, J = 1.9 Hz, 1H), 8.59 (d, 1-53 and 1-54 0 N OH(7. ..N\ _( *. 1 J = 5.1 Hz, 1H), 7.99-7.95 (m, 1H), 7.91-7.86 (m, 1H), 7.80-7.75 ./..,.. 7 1 ..- N 0 (M, 1H), 7.62 (d, J =
5.1 Hz, 1H), 7.53-7.50 (m, 2H), 7.48-7.41 iv -,, (m, 2H), 7.08-7.01 (m, 2H), 6.94 (d, J = 6.0 Hz, 1H), 4.72-4.59 n i-3 (m, 6H), 3.71 (s, 3H), 3.55-3.47 (m, 2H), 3.12-3.05 (m, 2H), .') n N 2.64-2.54(m, 1H), 2.52-2.44 (m, 2H). 2.25-2.15 (m, 1H), 1.02- )..) 6 0.95 (m, 3H).
=
)..) ....
o -.) c, Ge c, ,:.-.

54 I NMR (400 MHz, CD30D): 8 8.93-8.86 (m, 1H), 8.60-8.50 1-55 and 1-56 524.2 '14 0y,:*o;Nrõ..õN \
(in, 2H), 7.74-7.66 (in, 1H), 7.57 (d, J = 5.1 Hz, 1H), 7.22 (d, J =
HN '`... ......

1 5.9 Hz, 1H), 6.93 (s, 2H), 6.79 (d, J = 5.9 Hz, 1H), 4.66-4.56 (in, b.) =.- N 0 o 41 1H), 4.54-4.46 (m, 1H), 3.70 (s, 3H), 2.84-2.70 (m, 2H), 2.66- b.) , .
2.56 (in, 2H), 2.37 (s, 3H), 1.33-1.24 (in, 6H).
a, 4.
..1 W
Cii 55 . 509.2 ITINMR (400 MHz, CD30D): 8 8.81-8.76 (m, 1H), 8.59-8.53 1-55 and 1-57 OH
01, 1H), 8.22-8.16 (m, 1H), 7.63-7.56 (in, 3H), 7.25-7.21 (in, HON),N.;r:61:1-- 1H), 7.06-7.01 (m, 1H), 6.96-6.92 (m, 1H), 6.85-6.78 (m, 2H), .., N 0 - 'al 1 4.63-4.58 (m, 1H), 4.52-4.45 (m, 1H), 3.71 (s, 3H), 2.80-2.69 (m, 2H), 2.67-2.57 (m, 2H), 1.30-1.27 (m, 6H).
56 F F 685.3 'H NMR (400 MHz, CD30D): 8 8.67 (d, J = 2.3 Hz, 1H), 8.54 (d, 1-58 and 1-54 p 5;
0. ....r!,41 oHNic 14\ . J = 5.1 Hz, 1H), 7.94 (d, J = 2.7 Hz, 1H), 7.58 (d, J = 5.1 Hz, :
;II
. 1H), 7.50 (d, J = 2.3 Hz, 1H), 7.44 (dd, J = 8.9, 2.9 Hz, 1H), 7.28 .?.

to t=.> .H.71,.1 N 1 :-N 0 (d, J = 6.0 Hz, 1H), 7.07- 6.97 (m, 2H), 6.84 (d, J = 6.0 Hz, 1H), -....? 4.73-4.46 (in, 6H), 3.69 (s, 3H), 3.53-3.46 (m, 2H), 3.42- 3.33 .
.

e) (m, 2H), 3.14-3.00 (in, 2H), 2.95-2.82 (m, 2H), 2.59-2.40 (m, 17;
N 3H), 2.36-2.18 (m, 3H), 0.97 (d, J = 6.3 Hz, 3H).

57 o rt it, 663.3 'H NMR (400 MHz, CD30D): 8 8.68 (d, J = 2.3 Hz, 1H), 8.59 (d, 1-59 and 1-54 ....., .7 ..,.oFir,,,N
J = 5.1 Hz, 1H), 7.97 (d, J= 2.8 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.78 (dd, J = 6.1, 1.5 Hz, 1H), 7.61 n -...,....;,N o F

(d, J = 5.1 Hz, 1H), 7.57-7.49 (m, 2H), 7.45 (dd, J = 8.9, 2.8 Hz, n .k.T.) 1H), 7.42-7.35 (m, 1H), 7.03 (d, J = 8.9 Hz, 1H), 6.78 (d, J = 6.1 " =
k..) ) Hz, 1H), 4.74-4.57 (in, 6H), 3.71 (s, 3H), 3.55-3.46 (m, 2H), ...

-.) N 3.15-3.01 (m, 2H), 2.61-2.53 (m, 1H), 2.52-2.43 (m, 2H), 2.26- c, 6 2.15 (m, 11 1), 0.98 (d, J = 6.3 Hz, 3H).
Ge c, ,:.-.
o .
_ 58 I F 685.3 '14 NMR (400 MHz, CD30D): 8 8.67 (d, J = 2.3 Hz, 1H), 8.54 (t, 1-60 and 1-54 0 N, OHNr,N \ F
J = 4.9 Hz, 1H), 7.94 (d, J = 2.7 Hz, 1H), 7.59 (d, J = 5.1 Hz, 0 r,4 1 :-rs j 1H), 7.51 (d, J = 2.3 Hz, 1H), 7.44 (dd, J = 9.0, 2.9 Hz, 1H), 7.29 b.) o y (dd, J = 6.0, 0.5 Hz, 1H), 7.10- 6.97 (m, 2H), 6.85 (d, J = 6.0 Hz, b.) -.
1H), 4.72-4.45 (m, 6H), 3.69 (s, 3H), 3.55-3.45 (m, 2H), 3.21-a.
4.
3.16 (m, 2H), 3.12-2.97 (m, 4H), 2.61-2.52 (m, 1H), 2.49-2.32 w v.
N
6 (m, 4H), 2.24-2.15 (m, 1H), 0.96 (d, J = 6.3 Hz, 3H).
o 677.3 '11 NMR (400 MHz, CD30D): 6 8.73 (d, J = 2.3 Hz, 1H), 8.65- 1-59 and 1-2 I-j Nli r,,rH(7. .N *
N --- 8.53 (m, IH), 8.10-7.97 (m, IH), 7.92 (d, J = 8.4 Hz, 1H), 7.83 ,. N c;
..1--N 0 F
(d, J = 8.2 Hz, 1H), 7.78 (d, J = 4.7 Hz, 1H), 7.60 (d, J = 5.1 Hz, y 1H), 7.58-7.44 (m, 3H), 7.43-7.34 (m, 1H), 7.08-6.96 (m, 1H), 0 e 6.77 (d, J = 6.1 Hz, 1H), 4.75-4.52 (m, 6H), 3.89-3.56 (m, 5H), .:....--=1 N 3.21 (d, J = 6.3 Hz, 1H), 2.98-2.86 (m, 1H), 2.80-2.65 (m, 2H), P.
w 6 2.58-2.41 (m, 1H), 2.02-1.86 (m, 1H), 0.89 (d, J = 6.3 Hz, 6H).

.
:
60 i H al& F 681.2 '14 NMR (400 MHz, CD30D): 8 8.66 (d, J = 2.3 Hz, 1H), 8.57 (d, 1-61 and 1-54 0 N _..., mi =-. I 'N J = 5.1 Hz, 1H), 7.99-7.91 (m, 2H), 7.76 (d, J = 4.9 Hz, IH), 7.59 F (d, J = 5.1 Hz, 1H), 7.51-7.40 (in, 31-1), 7.36-7.25 (m, 1H), 7.01 y (d, J = 8.9 Hz, 1H), 6.79 (d, J = 6.1 Hz, 1H), 4.71-4.55 (m, 6H), 3.69 (s, 3H), 3.58-3.46 (m, 2H), 3.14-3.00 (m, 2H), 2.60-2.52 (m, N 1H), 2.49-2.41 (m, 2H), 2.25-2.15 (m, 1H). 0.96 (d, J = 6.3 Hz, v 6 3H).
n .3 n r.) =
r.) ....
..r.:
-a c, oe c, ,:.-.

61 I -----\- F 695.3 '14 NMR (400 MHz' - CD30D): 6 8.73 (d, J = 2.2 Hz' 1H), 8.59 (d, 1-61 and 1-2 0 N OH ...., N \ / ¨
\ i ,N ----- J = 5.1 Hz, 1H), 8.04-7.95 (m, 2H), 7.79 (d, J =
6.1 Hz, 1H), 7.61 ,H7NL.N 1 _.---N 0 F
(d, J = 5.1 Hz, 1H), 7.55-7.45 (m, 3H), 7.37-7.29 (m, 1H), 7.04 b.) o y (d, J = 8.8 Hz, 1H), 6.81 (d, J = 6.0 Hz, 1H), 4.75-4.57 (m, 6H), b.) , 3.83-3.74 (m, 1H), 3.72 (s, 3H), 3.26-3.16 (m, 1H), 2.97-2.88 a, A
-.1 W
N
(iii, 1H), 2.81-2.68 (m, 2H), 2.57-2.45 (m, 1H), 2.0-1.90 (m, v.
6 1H), 0.89 (d, J = 6.3 Hz, 6H).

62 I (:) 741.2 11-1 NMR (400 MHz, CD30D): 6 8.67 (d, J = 2.2 Hz, 1H), 8.55 (d, 1-62 and 1-54 ,..õ,..N,T ,,OHr.õ1,1 \
J = 5.1 Hz, 1H), 7.96 (s, 1H), 7.59 (d, J = 5.1 Hz, 1H), 7.52 (d, J
= 2.2 Hz, 1H), 7.45 (dd, J = 8.9, 2.8 Hz, 1H), 7.17 (d, J = 6.1 Hz, Bi.

..,.õ, 1H), 7.03 (d, J = 8.9 Hz, 1H), 6.79 (d, J = 5.9 Hz, 1H), 4.72-4.49 0 (m, 6H), 3.56-3.43 (m, 2H), 3.14-3.01 (m, 211), 2.83-2.73 (m, .?, . IJ 2H), 2.62-2.53 (m, 3H), 2.51-2.44 (m, 2H), 2.25-2.16 (m, 1H), ;I
.2 -=1 N
ro A
6 1.30 (d, J = 6.1 Hz, 6H), 0.97 (d, I = 6.3 Hz, 3H). 10 .
..

63 I 664.3 'HN MR (400 MHz, CD30D): -8 8.66 (d, J = 2.3 Hz, 111), 8.58 (d, 1-63 and 1-54 ON ,.. .,..0HrN.N \
i J = 5.1 Hz, 1H), 7.95 (d, J = 2.8 Hz, 1H), 7.90 (s, 1H), 7.62 (d, J
\ N ---N 1 1 % , 1 0 = 5.1 Hz, 1H), 7.49-7.42 (m, 2H), 7.03 (d, J =
8.9 Hz, 1H), 6.88 (s, 1H), 4.77- 4.47 (m, 6H), 3.70 (s, 1H), 3.55-3.46 (m, 2H), 3.16-2.99 (mz, 21-1), 2.87-2.74 (m, 2H), 2.68-2.60 (m, 2H), 2.60-2.54(m, 1H) 2.52-2.43 (m, 2H), 2.24-2.18 (m, 1H), 1.29 (d, J =
v N n 8.0 Hz, 6H), 0.97 (d, .1= 6.4 Hz, 3H).
.3 n r.) =
r.) ....
..r.:

c, oe c, :.-:

64 o 4 o 635.3 '14 NMR (400 MHz, CD30D): 8 8.68 (d, J = 2.0 Hz, 1H), 8.56 (d, I-! and 1-54 HN ' I HN J = 5.1 Hz, 1H), 7.95 (d, J = 2.8 Hz, 1H), 7.60 (d, J = 5.1 Hz, I 1H), 7.53 (d, J = 2.1 Hz, 1H), 7.45 (dd, J = 8.9, 2.8 Hz, 1H), 7.26 b.) ... , .,11 , .= N
0 o 1 (d, J = 5.9 Hz, 1H), 7.04 (d, J = 8.9 Hz, 1H), 6.95 (s, 1H), 6.82- b.) -..
, 6.77 (m, 1H), 4.74- 4.46 (m, 6H), 3.71 (s, 3H), 3.56-3.45 (m, ON
4.
.3) ) 2H), 3.13-3.02 (m, 2H), 2.96-2.88 (m, 2H), 2.83-2.76 (m, 2H), -1 VI
N
<11/4> 2.61-2.53 (m, 3H), 2.50-2.45 (m, 2H), 2.24-2.17 (m, 1H), 0.97 (d, o J = 6.4 Hz, 3H).
65 I 664.3 'NMR (400 MHz, CD30D): 8 9.11 (s, 1H), 8.94 (d, J = 2.3 Hz, 1-64 and 1-54 0 , N, 1 OH-... 6:1 ¨ FI 1H), 8.01-7.92 (m, 2H), 7.44 (dd, J = 8.9, 2.8 Hz, 1H), 7.23 (d, J
HN I = 6.0 Hz, 1H), 7.02 (d, J = 8.9 Hz, 1H), 6.97 (s, 1H), 6.91 (d, J =

L) 6.0 Hz, 1H), 4.73-4.56 (in, 6H), 3.71 (s, 3H), 3.55-3.44 (m, 2H), .?, 3.12-3.01 (m, 2H), 2.77-2.69 On, 2H), 2.64-2.60 On, 2H), 2.60-;II
-.2 -=1 t N ) 2.54 (m, 1H), 2.50-2.43 (m, 2H), 2.25-2.16(m, 1H), 1.30-1.26 .
tA
6 (in. 6H), 0.97 (d, J =
6.3 Hz, 3H). li o .0 I-677.3 ' NMR (400 MHz, CD30D): 8 8.69 (d, J = 2.2 Hz, 1H), 8.55 (d, 1-55 and ...s.
J = 5.1 Hz, 1H), 7.95 (d, J = 2.8 Hz, 1H), 7.59 (d, J = 5.1 Hz, i 1H), 7.53 (d, J = 2.3 Hz, 1H), 7.44 (dd, J = 8.9, 2.8 Hz, 1H), 7.22 . ., .. .. 7 ...41 0 1 (d, J = 6.0 Hz, 1H), 7.03 (d, J = 8.9 Hz, 1H), 6.94 (s, 1H), 6.79 -, (d, J = 5.9 Hz, 1H), 4.65-4.43 (m, 2H), 4.00-3.83 (m, 2H), 3.78-.) ) 3.60 (m, 5H), 3.49-3.36 (m, 1H), 3.09-2.95 (in, 3H), 2.81-2.54 v n N
= i (m, 7H), 2.42-2.26 (m, 1H), 2.16-2.03 (m, 1H), 1.94-1.79 (m, n 1H), 1.31-1.27 (m, 6H), 0.97-0.92 (m. 3H).

r.) =
r.) ....
..r.:

c, oe c, :.-:

67 I N¨ 646.3 '14 NMR (400 MHz, CD30D): 8 8.68 (s, 1H), 8.62-8.56 (m, 2H), 1-66 and 1-54 8.38-8.30 (m, 1H), 8.00-7.93 (m, 2H), 7.64-7.60 (m, 1H), 7.51-HN "`==

I 7.49 (m, 1H), 7.48 (s, 1H), 7.47-7.40 (m, 2H), 7.07-7.00 (m, 1H), b.) ..,.. .ji ..-N 0 p =-, I
7.00-6.94 (m, 1H), 4.73-4.55 (in, 6H), 3.71 (s, 3H), 3.54-3.47 (in, b.) .
, .
2H), 3.16-3.00 On, 2H), 2.62-2.54 On, 1H), 2.53-2.40 (m, 2H), a, 4.
.S)) 2.26-2.16 (in, 1H), 1.00-0.95 (in, 3H).

w v.
N

71 i'll 537.2 ' NMR (400 MHz, CD30D): 8 8.71-8.53 (m, 2H), 8.43 (s, 1H), 1-55 and 1-68 NN: 1 oftrySi-N \
8.00 (s, 1H), 7.76-7.57 (m, 2H), 7.26 (d, J = 5.1 Hz, 1H), 6.96 (s,1-1 HN
1 N 0 1H), 6.83 (d, J = 5.2 Hz, 1H), 4.61-4.40 (m, 4H), 2.83-2.60 (m, e'LN 4H), 1.57 (t, J = 6.7 Hz, 3H), 1.33-1.27 (m, 6H). 0 N¨N
C
;II
...
Ia ¨1 ro c., O ,..1::
3,r,.:õo ri-,,, N__\ 661.3 'H NMR (400 MHz, CD30D): 69.97 (s, 1H), 8.68 -8.64 On, 1-55 and 1-54 2H), 7.94 (d, J = 2.6 Hz, 1H), 7.63 (d, J = 5.2 Hz, 1H), 7.45-7.41 .

.1-,,,N 0 (in, 1H), 7.34 (d, J = 2.3 Hz, 1H), 7.26-7.23 (m, 1H), 7.03-6.99 ig -T) (m, 2H), 6.87-6.85 (m, 1H), 4.72-4.58 (m, 4H), 3.69 (s, 3H), 3.54-3.44 (in, 2H), 3.07-3.03 (in, 2H), 2.94-2.71 (in, 2H), 2.67-2.32 (m, 5H), 2.22-2.18 (m, 1H), 1.31-1.29 (m, 6H), 0.96 (d, J =
N
6 6.3 Hz, 3H).
o mig n 73 I 485.1 1H NMR (400 MHz, DMSO-d6): 8 8.53 (d, J = 5.1 Hz, IH), 8.33 I-1 and 1-69 .3 0 N 1 OHic., .N....., (s, 1H), 7.80 (d, J = 2.2 Hz, 1H), 7.75 (s, 1H), 7.46-7.44 (m, 2H), N
n t.) HN
=
I ,IssN 0 7.25 (d, J = 5.9 Hz, 1H), 6.83-6.74 (m, 2H), 5.02-4.97 (m, 1H) k4 ...
c1-1%
V 4.42-4.38 (m, 1H), 4.34-4.30 (m, 1H), 3.97 (s, 3H), 3.58 (s, 3H), -.) c, Ge 2.88-2.82 (m, 2H), 2.71-2.67 (n, 2H), 2.46-2.42 (n, 2H).
c, ,:.-.

74 645.3 '14 NMR (400 MHz, CD30D): 6 8.69 (d, J = 2.0 Hz, 1H), 8.60 (d, 1-70 and 1-54 1 \ J = 5.2 Hz, 1H), 8.00-7.83 (m, 4H), 7.62 (d, J = 5.2 Hz, 1H), _.,...214 0 7.55-7.42 (m, 4H), 7.37-7.33 (m, 1H), 7.04 (d, J
= 8.8 Hz, 1H), b.) o -.. 1 6.89 (d, J = 6.0 Hz, 1H), 4.75-4.53 (m, 7H), 3.72 (s, 3H), 3.59- b.) -.
3.44 (m, 2H), 3.13-3.05 (m, 2H), 2.63-2.54 (m, 1H), 2.50-2.47 o 4.

(in, 2H), 2.27-2.13 (in, 1H), 0.98 (d, J = 6.4 Hz, 3H).
VI
N

o 75 to.j,. F 663.2 'H NMR (400 MHz, CD30D): 6 8.68 (d, J = 2.2 Hz, 1H), 8.59 (d, 1-71 and 1-54 Filsr-Lj'.`6 :::. N-- J = 5.0 Hz, 1H), 8.00-7.94 (m, 2H), 7.89 (d, J = 5.8 Hz, 11-1), 7.62 ),N I N 0 (d, J = 5.1 Hz, 1H), 7.55-7.50 (in, 2H), 7.48-7.43 (m, 2H), 7.28 -L? (td, J = 9.4, 2.5 Hz, 1H), 7.04 (d, J = 9.0 Hz, 1H), 6.91 (d, J = 5.9 0 )r4) Hz, 1H), 4.72-4.54 On, 7H), 3.72 (s, 3H), 3.50 (dd, J = 19.0, 5.7 lill , 2H), 3.12- 3.04 (m, 2H), 2.58 (d, J = 8.1 Hz, 1H), 2.48 (s, P
. Hz .
-=1 ro -=1 2H), 2.28-2.15 (m, 1H), 0.98 (d, J = 6.2 Hz, 3H).
.g 1 6o 76 1 646.2 'H NMR (400 MHz, CD30D): 6 8.66 (d, J = 4.8 Hz, 1H), 8.58 (s, 1-70 and 1-72 .
ill 1H), 8.05 (d, J = 3.2 Hz, 1H), 7.94 (d, J = 8.8Hz, 1H), 7.89-7.85 ' 2 -N 0 (m, 2H), 7.72 (d, J = 5.2 Hz, 1H), 7.52-7.44 (m, 3H), 7.37-7.33 (m, 1H), 7.18 (d, J = 8.8 Hz, 1H), 6.92 (d, J = 6.4 Hz, 1H), 4.74-4.55 (m, 5H), 3.89 (s, 3H), 3.52-3.48 (mHz, 1H), 3.22-3.07 (m, N 2H), 2.55-2.44 (m, 1H), 2.40-2.33 (m, 2H), 2.03-1.98 (m, 1H).
1.88 (s, 2H), 1.04 (ci. J = 6.0 Hz, 3H).
v n .3 n it I 508.2 'FINMR (400 MHz, CD30D): 6 8.52 (d, J 4.8 Hz, 1H), 7.52 (d, 1-55 and 1-73 ay..N,i, (..oFirN \
J = 5.2 Hz, 111), 7.44 (d, J = 2.0 Hz, 1H),7.41 (d, J = 2.0 Hz, -.) FIN '''irLr-= ' .-4-.- 1H), 7.34-7.26 (m, 4H), 7.22 (d, J = 6.0 Hz, 1H), 7.02-6.95 (m, c, c, 1H), 6.93 (s, 1H), 6.77 (d, J = 6.0 Hz, 1H), 4.56 (d, J = 11.6 Hz, 1H), 4.48 (d, J = 12.0 Hz, 1H), 3.70 (s, 3H), 2.74 (d, J = 3.2 Hz, ,:.-.

2H), 2.62 (s, 2H), 1.29 (d, J = 5.6 Hz, 6H).
78 ois) 663.3 '11 NMR (400 MHz, CD30D): 8 8.70-8.64 (m, 1H), 8.57-8.51 1-74 and 1-54 0 0 4 0 ,,....
.
=
(in, 1H), 7.97-7.91 (m, 1H), 7.60-7.56 (m, 1H), 7.54-7.50 (m, b.) , N. N ---- 1H), 7.46-7.42 (m, 1H), 7.28-7.23 (m, 1H), 7.05-7.00 (in, 1H), .
HN I
a.
4.
.., N 0 -..i ....,- .7 6.97-6.93 (m, 1H), 6.82-6.76 (m, 1H), 4.72-4.67 (m, 2H), 4.65- w v.
4.60 (m, 21-1), 4.59-4.57 (m, 1H), 4.50-4.44 (m, 1H), 3.69 (s, 3H), ( ) 3.53-3.44 (m, 2H), 3.12-3.01 (m, 2H), 2.98-2.87 (m, 1H), 2.81-N 2.62 (m, 2H), 2.60-2.53 (m, 1H), 2.51-2.42 (m, 2H), 2.37-2.25 6 (in, 1H), 2.23-2.16 (in, 1H), 2.08-1.89 (m, 2H), 1.53-1.39 (m, o 1H), 1.21-1.13 (m, 3H), 0.98-0.94(m, 3H).
79 1 664.3 'H NMR (400 MHz, CD30D/CDC13=1/1): 8 8.68-8.62 (in, 1H), 1-75 and 1-54 0 )0 i ;,;LiTrilSj- 8.62-8.55 (m, 1H), 8.34-8.28 On, 1H), 8.03-7.95 On, 1H), 7.70- :5;
.
;11 . 7,N 0 7.65 (m, 1H), 7.62-7.59 (m, 1H), 7.46-7.41 (m, 1H), 7.13-7.07 .2 to CO
yl (n, 1H), 7.05-6.96 (m, 1H), 4.75-4.72 (in, 2H), 4.70-4.63 (in, il;
z 2H), 4.61-4.53 (m, 2H), 3.74 (s, 3H), 3.59-3.52 (m, 1H), 3.51-.
.

I-N ' 3.43 (m, 1H), 3.15-3.05 (m, 2H), 2.90-2.81 (m, 2H), 2.71-2.64 6 (m, 2H), 2.64-2.58 (m, 1H), 2.56-2.45 (m, 2H), 2.27-2.16 (m, 1H), 1.34 (s, 6H), 1.05-0.95 (m, 3H).
68a I 551.2 1-55 and 1-67 ,p0 r...-... N \
HN '''="-*N'-' '"'-'....kr. N ----Concentrated v I
n hydrochloric .3 \ r;i acid, n IANi methanol, k..) =
k..) ...
stirring at c, Ge room c, ,4.-.
temperature to remove --Boc 1-54 and 1-79 0 O N 663.3 1H NMR (400 MHz, CD30D) 8 8.67 (d, J = 2.2 Hz, 1H), 8.53 (d, b.) I so tirc J = 5.1 Hz, 1H), 7.94 (d, J = 2.6 Hz, 1H), 7.57 (d, J = 5.1 Hz, -2 - , - .
HN I 1H), 7.52 (d, J = 2.3 Hz, 1H), 7.43 (dd, J = 9.0, 2.7 Hz, 1H), 7.38 .
C.' 4.
,- N 0 -..1 1 (d, J = 6.2 Hz, 1H), 7.02 (d, J = 8.9 Hz, 1H), 6.96 (s, 1H), 6.78 v.
.., (d, J = 6.1 Hz, 1H), 4.73-4.44 (m, 6H), 3.69 (s, 3H), 3.57-3.45 ) (m, 2H), 3.14-3.00 (m, 2H), 2.97-2.88 (m, 2H), 2.79-2.71 (m, N 2H), 2.63-2.55 (m, 1H), 2.52-2.43 (m, 2H), 2.27-2.16 (m, 1H), 6 1.97-1.87 (m, 2H), 1.83 -1.66 (m, 4H), 0.96 (d, J = 6.3 Hz, 3H).
a 93 I 651.3 1-54 and 1-80 'H NMR (400 MHz, CD30D) 8 8.67 (d, J = 2.3 Hz, 1H), 8.55 (d, /.1 tp `-. 1 4 \ J = 5.1 Hz, 1H), 7.95 (d, J = 2.8 Hz, 1H), 7.59 (d, J = 5.1 Hz, .?, HN , .:"2 .., I ill), 7.51 id, J = 2.3 Hz, 1H), 7.44 (dd, J = 8.9, 2.8 Hz, 1H), 7.32 i'FI
-. 11 -=1 / N 0 No ''.. .1, I (d, J = 6.0 Hz, 1H), 7.03 (d, J = 8.9 Hz, 1H), 6.96 (s, 1H), 6.85 -.
:7:
(d, J = 6.0 Hz, 1H), 4.80-4.76 (m, 2H), 4.72-4.47 (m, 6H), 4.10-, e .
.1 ) 4.01 (m, 2H), 3.70(s, 3H), 3.56-3.46 (m, 2H), 3.13-3.00 (m, 2H), , "
N 2.95-2.85 (m, 2H), 2.61-2.54 (m, 1H), 2.52-2.43 (m, 2H), 2.26-2.17 (in, 1H), 0.97 (d, J = 6.3 Hz, 3H).
so , 100 i 664.3 '11 NMR (400 MHz, CD30D): 8 8.68 (d, J = 2.0 Hz, 1H), 8.54 (d, 1-54 and 1-55, 0 N 0 ms0,11r,N,...91¨
J = 5.1 Hz, 1H), 7.94 (d, J = 2.7 Hz, 1H), 7.58 (d, J = 5.1 Hz, NaBD4 V
1 N 0 1H), 7.52 (d, J = 2.2 Hz, 1H), 7.44 (dd, J = 8.9, 2.6 Hz, 1H), 7.22 n i-3 --.14 -1 (d, J = 5.9 Hz, 1H), 7.02 (d, J = 8.9 Hz, 1H), 6.93 (s, 1H), 6.78 n (d, J = 5.9 Hz, 1H), 4.74-4.43 (m, 5H), 3.69 (s, 3H), 3.55- 3.44 k..) =
t) ) (m, 2H), 3.13-2.98 (m, 2H), 2.82-2.68 (in, 2H), 2.63-2.53 (in, k4 -.N
..=
6 3H), 2.46 (m, 2H), 2.20 (in, 1H), 1.28 (d, J = 6.4 Hz, 6H), 0.96 -4 c, c, a (d, J = 6.3 Hz, 3H).
,4.-.

101 i 665.4 ' NMR (400 MHz, CD30D): 8 8.68 (d, J = 2.2 Hz, 1H), 8.53 (d, 1-186 and I-o ,),4 1 D (21;:c.:,6 J = 5.1 Hz, 1H), 7.94 (d, J = 2.7 Hz, 1H), 7.58 (d, J = 5.1 Hz, 55, NaBD4 HN I 1H), 7.52 (d, J = 2.1 Hz, 1H), 7.43 (dd, J = 8.9, 2.7 Hz, 1H), 7.21 0 b.) ,)) o 1 (d, J = 5.9 Hz, 1H), 7.02 (d, J = 8.9 Hz, 1H), 6.92 (s, 1H), 6.78 )..) -, .,.
(d, J = 5.9 Hz, 1H), 4.73-4.43 (m, 5H), 3.68 (s, 3H), 3.53-3.43 a, 4.
V ) (m, 1H), 3.11- 2.98 (m, 2H), 2.80-2.68 (m, 2H), 2.66-2.52 (m, -1 w v.

31-1), 2.50-2.39 (m, 2H), 2.24-2.14 (m, 111), 1.28 (d, J = 6.4 Hz, o 6H), 0.96 (d, J = 6.3 Hz, 3H).
104 I 678.3 .

I --- 1H NMR (400 MHz, CD30D) 8 8.66-8.62 (m, 1H), 8.55-8.51 (m, 1-54 and 1-82 HN`. 4tr i 1H), 7.96-7.92 (m, 1H), 7.59-7.57 (m, 1H), 7.50-7.49 (m, 1H), ,.- N 0 ""..y 1 7.45-7.41 (m, 1H), 7.07-6.98 (m, 2H), 4.71-4.66 (m, 2H), 4.64-=,..
4.54 (m, 4H), 3.68 (s, 3H), 3.53-3.45 (m, 2H), 3.11-3.00 (m, 4H), ;II
.
P.
co .
= 2.63-2.52 (m, 6H), 2.50-2.41 (m, 2H), 2.24-2.16 (m, 1H), 1.30 (s, .
N :7 6:
6H), 0.99-0.94 (m, 3H).
.
0 .

z 105 I 665.3 1-54 and 1-83 o N F .. 1H NMR (400 MHz, CD30D) 8 8.70-8.51 (m, 2H), 7.92-7.90 (m, 1H), 7.55-7.53 (m, 1H), 7.38 (d, J = 6.9 Hz, 11-1), 7.27 (s, 1H), 7.21-7.11 (m, 1H), 6.97-6.95 (m, 1H), 6.90-6.88 (m, 1H), 6.79-6 .77 (m, 1H), 5.51-5.20 (m, 2H), 4.69-4.51 (m, 4H), 3.64 (s, 3H), mig n ) 3.52-3.39 (m, 2H), 3.00-2.97 (m, 2H), 2.88-2.85 (m, 1H), 2.72- .3 n 2.28 (m, 6H), 2.18-2.16 (m, 1H), 1.28-1.24 (m, 6H), 0.93 (d, J :

N
t.) 6 6.2 Hz. 3H).
=
k..) ...
o -.) c, Ge c, ,:.-.

0....., µ
114 I 677.4 ITINMR (400 MHz,CD30D) 8 8.63-8.59 (m, 1H), 8.53-8.47 (m, 1-54 and 1-84 .N,.. 15.0Hr....,,,. ,N \
,.. I 111), 7.93-7.89 (m, 1H), 7.50-7.47 (m, 1H), 7.46-7.42 (m, 1H), 0 riN''.----r" -----7.35-7.27 (m, 1H), 7.25-7.15 (m, 1H), 7.04-6.99 (m, 1H), 6.93-b.) o k.4 -1) 6.90 (m, 1H), 6.81-6.66 (m, 1H), 5.16-4.97 (m, 1H), 4.72-4.6.7 .
, C^ ' (m, 2H), 4.64-4.57 (m, 2H), 3.71-3.67 (m, 3H), 3.53-3.43 (m, 4.
..1 iFS) ) 2H), 3.10-3.01 (m, 2H), 2.79-2.68 (m, 2H), 2.66-2.59 (m, 2H), w v.
N 2.59-2.54 (m, 1H), 2.49-2.43 (m, 2H), 2.23-2.14 (m, 1H), 1.40-1.34 (m, 3H), 1.30-1.27 (m, 6H), 0.97-0.93 (m, 31-1).
o 0 4 oili,N . 664.2 1-54 and 1-85 c... , =

111 NMR (400 MHz, CD3013/CDC13 I/1): 8 8.91 (s, 1H), 8.60 (s, ,.._ 1 N ---HN 1H), 8.56 (d, J = 4.9 Hz, 1H), 8.06 (s, 1H), 7.95 (s, 1H), 7.87 (d, 0 I ..tsi o F
J = 7.8 Hz, 1H), 7.72 (s, 1H), 7.64 (t, J = 7.9 Hz, 1H), 7.57 (s, :5;
i 1H), 7.51 (t, J = 7.9 Hz, 1H), 7.41 (d, J = 8.7 Hz, 11-1), 6.98 (d, J
;I
.
.2 co .
- = 8.9 Hz, 1H), 4.71-4.58 (m, 6H), 3.70 (s, 3H), 3.54-3.42 (m, .
N
2H), 3.11-2.99 (m, 2H), 2.61-2.52 (m, 1H), 2.52-2.40 (m, 2H), .
.
6 2.22-2.12 (in, 1H), 0.96 (d, J = 6.0 Hz, 3H). 0 I-o 1-54 and 1-86 664.2 ITINMR (400 MHz, CD30D): 8 8.64 (d, J = 2.3 Hz, 1H), 8.58--, 1 4 ----HN 8.47 (m, 2H), 7.94 (d, J = 2.5 Hz, 1H), 7.58 (d, J = 5.1 Hz, 1H), I y ...N 0 -.-' 7.49 (d, J = 2.3 Hz, 1H), 7.43 (dd, J = 9.0, 2.8 Hz, 1H), 7.09-6.98 i v (m, 2H), 4.74-4.54 (m, 6H), 3.68 (s, 3H), 3.59-3.44 (m, 2H), n = 3 3.12-3.00 (m, 4H), 2.80-2.72 (in, 2H), 2.65-2.58 (in, 1H), 2.51 (t, n )..) J = 4.9 Hz, 2H), 2.28-2.19 (m, 1H), 1.98-1.88 (m, 2H), 1.83-1.70 =
N
r.) 6 (m, 4H), 0.96 (d, J =
6.4 Hz, 3H). ....
..=

c, o Ge c, ,4.-.

1-54 and 1-87 CN,.. ,,011% jõ.4-,N
646.2 1H N MR (400 MHz, DMSO-d6): 6 9.29 (s, 1 il), 8.61 (d, J - 2.3 Hz, I H), 8.54 (d, J = 5.1 Hz, 1H), 8.46 (s, 1H), 8.28 (d, J = 8.4 ')Iki `.e'rNI 0 Hz, 1H), 7.91 (d, J =
8.0 Hz, 1H), 7.82 (d, J = 2.8 Hz, IH), 7.60- b.) =
b.) ...,) 7.42 (m, 5H), 7.34 (dd, J = 9.0, 2.9 Hz, 1H), 7.22 (d, J = 9.1 Hz, -.
C' 1H), 4.97 (t, J = 5.2 Hz, 1H), 4.54-4.35 (m, 6H), 3.69-3.62 (m, 4.
..1 W
. ) 1H), 3.57 (s, 3H), 3.46-3.40 (m, 1H), 3.09-3.03 (m, 1H), 2.95- v.
6 N 2.87(m, 1H), 2.54-2.49 (m, 1H), 2.32-2.23 (m, 2H), 2.19-2.09 (m. 1H), 0.89 (d, J = 6.4 Hz. 3H).
o 157 I 650.2 1-54 and I-88 ,_ I Ili NMR (400 MHz, CD30D) 8 8.69-8.61 (m, III), 8.57-8.50 (m, FIN"-z-----"---r" -----\
IH), 8.44 (s, 1H), 7.95 (s, 1H), 7.64-7.55 (m, 1H), 7.50 (s, 1H), 7.47-7.39 (m, IH), 7.08-6.99 (m, 2H), 4.71-4.67 (m, 2H), 4.64-..
sl :5;
.
.
4.56 (m, 4H), 3.69 (s, 3H), 3.53-3.45 (m, 2H), 3.11-3.01 (m, 2H), .?.
k.) ) 2.92-2.83 (m, 2H), 2.74-2.64 (m, 2H), 2.61-2.52 (m, 1H), 2.52- il;
z 2.40 (m, 2H), 2.25-2.14 (m, 1H), 2.03-1.93 (m, 2H), 1.91-1.79 .
N

6 (m, 2H), 1.02-0.89 (m, 3H). .
...
"
o 1-54 and 1-89 CN
664.2 .., ,.0114.71gDo 1H NMR (400 MHz, CD30D) 8 8.66-8.60 (m, I H), 8.55-8.49 (m, HN's=----"--INI --' 111), 7.97-7.88 (m, 1H), 7.60-7.53 (m, 1H), 7.52-7.46 (m, IH), 7.45-7.38 (m, 1H), 7.05 (s, 1H), 7.03-6.96 (m, 1H), 4.71-4.65 (m, v n 2H), 4.64-4.52 (m, 4H), 3.67 (s, 3H), 3.53-3.43 (m, 2H), 3.19-n ) 3.11 (m, 2H), 3.10-2.99 (m, 2H), 2.74-2.64 (m, 5H), 2.57-2.51 2 r.) =
011, 1H), 2.50-2.39 (m, 2H), 2.23-2.14 (m, 1H), 1.98-1.88 (m, "
N
....
6 2H), 1.84-1.74 (m, 2H), 1.00-0.89 (m, 3H). ..r.:
-.) c, Ge o c, ,:.-.

160 1 0 N OH 649.2 1-54 and 1-90 õ (RS) 11-1 NMR (400 MHz, CD30D): 8 8.67 (d, J = 2.0 Hz, 1H), 8.53 (d, ,1-15,NLI N I
..-- N 0 J = 5.0 Hz, 1H), 7.94 (s, 1H), 7.57 (d, J = 5.0 Hz, 1H), 7.52 (d, J
= 2.1 Hz, 1H), 7.43 (dd, J = 8.9, 2.7 Hz, 1H), 7.22 (d, J = 5.8 Hz, o b.) y _.
I H), 7.02 (d, J = 9.0 Hz, 1H), 6.91 (s, 1H), 6.77 (d, J = 5.8 Hz, .
C.' 4, ) I H), 4.72-4.44 (m, 6H), 3.68 (s, 3H), 3.54-3.44 (m, 2H), 3.13 - -1 w v.
N 2.93 (m, 5H), 2.62-2.34 (m, 5H), 2.26-2.15 (m, 1H), 1.28-1.23 6 (m, 3H), 0.95 (d, J =
6.3 Hz, 3H).
o 1-54 and 1-91 Qky,N, .,...OH irTriip 607.2 'Fl NMR (400 MHz, CD30D): 6 8.67 (d, J = 1.9 Hz, 1H), 8.53 (d, 1 J - 5.1 Hz, 1H), 7.94 (d, J = 2.8 Hz, 11-1), 7.57 (d, J = 5.1 Hz, F 1H), 7.50 (d, J= 2.1 Hz, 1H), 7.44 (dd, J = 8.9, 2.7 Hz, 1H), 7.14 p ..),,. ,N =:õ....;õN 0 o y (d, J = 6.1 Hz, 1H), 7.02 (d, J = 8.9 Hz, 1H), 6.69 (d, J = 6.0 Hz, .
.
sl I..
I..I 1H), 4.71-4.47 (m, 6H), 3.69 (s, 3H), 3.53-3.45 (m, 2H), 3.12- .2 ce .
w t) ) 3.00 (in, 2H), 2.78-2.67 (in, 2H), 2.65-2.54 (m, 3H), 2.49-2.41 N (in, 2H), 2.24-2.14 (in, 1H), 1.98-1.87 (m, 2H), 1.87-1.76 (m, .

.
2H), 0.96 (d, J = 6.3 Hz, 3H).
.
o 163 I 598.2 1-134 and 1- ' 0,...s.,.N, ,,Ol..^,,,N
1H NMR (400 MHz, CD30D) 8 8.57- 8.46 (m, 1H), 8.40 (s, 1H), 88 7.93 (s, 1H), 7.62-7.48 (m, 1H), 7.38 (s, 1H), 7.02 (s, 1H), 5.83 =-,,,,, ' N 0 N (s, 1H), 4.59-4.44 (in, 2H), 4.04-3.93 (m, 2H), 3.73-3.61 (m, 5H), v ni n 3.59-3.52 (m, 2H), 3.32 (s, 3H), 3.03-2.94 (m, 2H), 2.89-2.80 (m, .3 n N--) 2H), 2.78-2.71 (m, 2H), 2.71-2.63 (m, 2H), 2.00-1.90 (m, 2H). 2 1.89-1.79 (m, 2H).
k..) =
k..) ...
o \

c, Ge c, ,4.-.

1-136 and I-596'2 1H NMR (400 MHz, CD3013/CDC13 I/I) 6 8.57-8.50 (in, 1H), iv \

HN , N --- 8.36 (s, 1H), 7.95-7.89 (m, 1H), 7.60-7.52 (m, 1H), 7.45-7.36 (m, o -,....õ..I: N o 1H), 7.05 (s, 1H), 5.85 (s, 1H), 4.76-4.72 (m, 2H), 4.65-4.61 (m, b.) =
EN
b.) 2H), 4.55-4.48 (m, 2H), 4.09-4.00 (m, 2H), 3.78-3.71 (m, 1H), -.
N-) a, 3.68 (s, 3H), 3.58-3.53 (m, 2H), 2.89-2.81 (m, 4H), 2.72-2.66 (m, 4.
..1 W
2H), 2.00-1.93 (m, 2H), 1.90-1.80 (m, 2H).
v.
do 167 1 615.2 1-134 and 1-0 N.,. 01-1(.., .N.....\
I 111 NMR (400 MHz, CD30D):8 8.52 (d, J = 5.1 Hz, 1H), 7.96 (d, 91 HN
I..-J = 2.2 Hz, 1H), 7.55 (d, J =
5.1 Hz, 1H), 7.41 (d, J = 2.2 Hz, N o F
Err 1H), 7.14 (d, J = 6.0 Hz, 1H), 6.68 (d, J = 6.0 Hz, 1H), 5.85 (s, 1H), 4.61-4.45 (m, 2H), 4.05-3.98 (m, 2H), 3.74-3.70 (m, 2H), N--) 3.67 (s, 3H), 3.60-3.55 (m, 2H), 3.33 (s, 3H), 3.05-2.98 (m, 2H), ...
"4 2.79-2.70 (m, 4H), 2.64-2.57 (m, 2H), 1.96-1.79 (m, 4H).
..0 co 4.
0\
to ri =

"
0 NI 597.2 I-134 and 1- .
OH
168 IH NMR (400 MHz, CD30D): 68.52 (dd, J = 5.1, 0.5 Hz, 1H), 90 7.96 (d, J = 2.3 Hz, 1H), 7.55 (d, J = 5.1 Hz, 1H), 7.42 (d, J = 2.2 HN
I -N 0 Hz, 1H), 7.21 (d, J =
5.9 Hz, 11-1), 6.91 (s, 11-1), 6.76 (d, J = 5.9 i Hz, 1H), 5.84 (s, 1H), 4.58-4.41 (m, 2H), 4.00 (t, J = 5.6 Hz, 2H), E
3.72-3.69 (m, 2H), 3.67 (s, 3H), 3.57 (t, J = 5.3 Hz, 2H), 3.33 (s, N-) 3H), 3.13-2.93 (m, 5H), 2.75 (t, J = 5.3 Hz, 2H), 2.54-2.33 (m, v n .3 2H), 1.27-1.23 (m, 3H).

n \

r.) =
r.) ....
..r.:

c, oe c, :.-:

176 I 558.2 1-144 and I-0 N., ,,OH I 1-1 N MR (400 MHz, CD30D/CDC13=3/1) 8 8.50 (d, J = 7.0 Hz, 1H), 7.93 (d, J = 5.8 Hz, 1H), 7.53 (d, J = 5.1 Hz, 1H), 7.43-7.41 I N 0 F (m, 1H), 7.10-7.00 (m, 1H), 6.63 (d, J = 6.0 Hz, 1H), 5.82 (s, b.) o bj \ , 1H), 4.76-4.74 (m, 2H), 4.57-4.43 (m, 2H), 4.11-3.94 (m, 4H), -.
N
ON
4.
3.68 (s, 3H), 2.76-2.54 (m, 4H), 1.97-1.76 (m, 4H).
-.1 w v.

0 NI 611.0 1-134 and I-Oli HN r;7. N I H NMR (400 MHz, CD3ODICDC13=1/1) 8 8.59-8.49 (m, 1H), 59 N F
\I N1)( 7.94-7.88 (m, 1H), 7.86-7.77 (m, 2H), 7.71-7.66 (m, 1H), 7.57-, \
I
N 0 7.53 (m, 1H), 7.52-7.47 (m, 1H), 7.41-7.37 (m, 1H), 7.37-7.32 \ i N (11, 1H), 6.78-6.62 (m, 1H), 5.82 (s, 1H), 4.66-4.59 (in, 1H), 4.56-4.50 (m, 1H), 4.07-3.98 (m, 2H), 3.74-3.69 (m, 2H), 3.68 (s, N--) i-i 3H), 3.59-3.54 (m, 2H), 3.34 (s, 3H), 3.06-2.98 (m, 2H), 2.79- .
,., I-.4;.
2.72 (m, 2H).
.?.
'20 0 .
tA
\
.
t7:
.
178 I 609.0 1-136 and 1- O. _N
IHNMR (400 MHz, CDC13) 8 8.60-8.52 (m, 1H), 8.01-7.96 (m, ..

1H), 7.88-7.85 (m, 1H), 7.67-7.63 (m, 2H), 7.52-7.48 (m, 2H), o F 7.38-7.34 (m, 2H), 6.65-6.57 (m, 1H), 5.71 (s, 1H), 4.75-4.71 (m, 2H), 4.67-4.64 (m, 2H), 4.62-4.57 (m, 2H), 4.45-4.36 (m, 1H), ( ) N¨ 4.13-4.03 (m, 2H), 3.79-3.71 (m, 1H), 3.70 (s, 3H), 3.56-3.52 (m, 1--( 2H), 3.48 (s, 1H), 2.82-2.78 (m, 2H).
0-' v n i-3 1-145 and 1- n 0 N OH 530.2 1H NMR (400 MHz, CD30D) 8 8.48 (d, J = 5.1 Hz, 1H), 7.79 (s, 1H), 7.53-7.45 (m, 2H), 7.27 (d, J = 5.5 Hz, 1H), 7.14-7.12 (m, )..) I NI'rryji-$¨D
91 =
k..) ...
....
HN

0 F 1H), 7.05-7.03 (m, 1H), 6.65 (d, J = 6.0 Hz, 1H), 4.56-4.39 (m, -a c, ,:oe l 2H), 4.10 (q, J = 7.3 Hz, 2H), 3.66 (s, 3H), 2.77-2.54 (m, 4H), c, .-.
N-N
1.96-1.76 (m, 4H), 1.41 (t, J = 7.3 Hz, 3H).

18 I I 540.0 '14 NMR (400 MHz, CDC13): 6 8.54 (d, J = 5.1 Hz, 1H), 7.99 (d, 1-144 and I-(111...N.,.. ., 0Hr.,,..<-.. N \ (RS) I J = 2.3 Hz, 1H), 7.74 (d, J = 2.0 Hz, 1H), 7.50-7.40 (m, 2H), 7.01 90 (s, 1H), 6.91 (d, J = 5.9 Hz, 1H), 6.63 (d, J = 6.0 Hz, 1H), 5.70 (s, b.) I E 4.39- N
1H) 5.11-5.02 (m 1H) 4.78 (s 2H) 4.53-4.45 (m 1H) ,..N 0 o , , , , , , , b.) Ni -.
I-.
4.28 (m, 1H), 4.11-4.02 (m, 4H), 3.70 (s, 3H), 3.10 -2.94 (m, a, 4.
..1 0-1 3H), 2.51-2.35 (m, 2H), 1.27 (d, J = 6.2 Hz, 3H). w v.
182 HO 679.3 1-54 and 1-92, (RS Ili N MR (400 MHz, CD30D): 6 8.68 (t, J = 2.1 Hz, 1H), 8.54 Removing ir.7.. .N \
(dd, J = 5.1, 1.6 Hz, 1H), 7.95 (d, J = 2.7 Hz, 1H), 7.58 (d, J= 5.1 I N ---Ac during the Hz, 1H), 7.55-7.48 (n, 1H), 7.44 (dd, J = 8.9, 2.8 Hz, 1H), 7.39 '.. I
(d, J = 5.9 Hz, 1H), 7.02 (d, J = 8.9 Hz, 1H), 6.91 (s, 1H), 6.83 (dd, J = 5.9, 1.9 Hz, 1H), 4.76-4.45 (in, 7H), 3.72-3.66 (in, 3H), Suzuki reaction ) 5;
3.57-3.45 On, 2H), 3.14-3.03 (m, 2H), 2.77-2.68 (m, 1H), 2.65-:
;II
I-. N 2.58 (n, 1H), 2.55-2.45 (n, 3H), 2.28-2.19 (m, 1H), 1.25-1.17 .?.
co 6 (n, 6H), 0.96 (d, J =
6.3 Hz, 3H). .
'i a.

183 I 620.4 1-146 and I-ON
,,.,.,.. õOFIN
,... I IHNMR (400 MHz, CDC]) 6 8.80-8.75 (in, 1H), 8.63-8.57 (m, 59 HN'''s-1-.- N 1H), 8.24-8.12 (m, 1H), 7.91 (s, 1H), 7.89-7.86 (n, 1H), 7.86-F
7.84 (in, 1H), 7.68-7.64 (in, 1H), 7.62-7.58 (in, 1H), 7.53-7.49 -XI (in, 2H), 7.39-7.35 (in, 2H), 6.86-6.81 (n, 1H), 6.66-6.60 (in, I H), 4.73-4.70 (n, 2H), 4.67-4.58 (n, 2H), 4.58-4.55 (in, 2H), V
N 4.46-4.37 (m, 1H), 3.83-3.77 (n, 1H), 3.76-3.72 (n, 5H), 3.69- n .3 6 3.64 (m, III), 3.27-3.22 (m, 211). n r.) =
r.) ....
..r.:

c, oe c, t.-:

184 I f-----\ 650.3 1-54 and 1-93 0.......õ_,A,, ....01-1,,,,...N,N,, / Ili NMR (400 MHz, CD30D) 8 8.61-8.57 (m, 1H), 8.57-8.52 (m, 1H), 7.96-7.90 (in, 1H), 7.78-7.70 (in, 1H), 7.58-7.55 (m, 1H), 7.50-7.46 (m, 1H), 7.40-7.34 On, 1H), 6.97-6.86 On, 2H), 4.72-b.) =
bj i..i y 4.68 (m, 2H), 4.62-4.53 (m, 3H), 4.47-4.41 (m, 1H), 3.69 (s, 3H), -.
C.' 3.54-3.48 (m, 1H), 3.46-3.38 (m, 1H), 3.09-3.01 (m, 2H), 2.88-4.
..1 W
. ) 2.79 (in, 2H), 2.69-2.62 (in, 2H), 2.59-2.53 (m, 1H), 2.50-2.41 v.
N (m, 2H), 2.21-2.13 (m, 1H), 1.94-1.78 (m, 4H), 0.98-0.92 (m, 6 3H).

0 4 668.2 1-54 and 1-94 01-Litcr4DN \
I Ili NMR (400 MHz, CD30D) 8 8.66-8.61 (n, 1H), 8.57-8.52 (m, HN
1 F 1H), 8.39-8.34 (in, 1H), 7.98-7.93 (in, 1H), 7.61-7.57 (m, 1H), 0 :5;
=,-.7 7.51-7.47 (m, 1H), 7.47-7.41 On, 1H), 7.06-7.00 On, 1H), 4.72- ...
i .--4 . -. 4.67 (m, 21-1), 4.66-4.54 (m, 4H), 3.70 (s, 3H), 3.53-3.46 (m, 2H), .?.
ce 3.15-2.99 (m, 2H), 2.91-2.81 (m, 2H), 2.68-2.60 (m, 2H), 2.60-z 2.53 (m, 1H), 2.52-2.43 (m, 2H), 2.24-2.17 (m, 1H), 2.01-1.92 .
N

6 (m, 2H), 1.92-1.80 (m, 2H), 1.02-0.94 (m, 3H). .
...
"

187 I663.2 'H NMR (400 MHz, CD30D): 8 8.67 (d, J = 2.3 Hz, 1H), 8.54 (d, 1-54 and 1-95 0 N OHr., N Q_õ
J = 5.1 Hz, 1H), 7.94 (d, J = 2.8 Hz, 1H), 7.58 (d, J = 5.1 Hz, HN
I 1H), 7.52 (d, J = 2.3 Hz, 1H), 7.44 (dd, J = 9.0, 2.9 Hz, 1H), 7.24 y (d, J = 5.9 Hz, 1H), 7.02 (d, J = 8.9 Hz, 1H), 6.93 (s, 1H), 6.79 v n (d, J = 6.0 Hz, 1H), 4.73-4.44 (m, 6H), 3.69 (s, 3H), 3.53-3.45 n (m, 2H), 3.12-3.01 (m, 2H), 2.92-2.63 (m, 3H), 2.61-2.52 (m, r.) =
6 ,H), 2.50-2.42 (m, 2H), 2.32-2.17 (m, 2H), 2.11-1.81 (in, 2H), k.) ...
..=
1.65-1.49 (m, 1H), 1.11 (dd. J = 6.6, 1.5 Hz, 3H), 0.96 (d, J = 6.3 o c, Ge Hz, 3H).
c, ,:.-.

0 659.2 Ili NMR (400 MHz, CD30131CDC13=1/1) 8 8.64 (d, J
= 2.2 Hz, 1-54 and 1-96 HN N, Ir0HNN ---- 1H), 8.57 (d, J = 5.1 Hz, 1H), 7.95 (d, J = 2.7 Hz, 1H), 7.73 (dd, J

I r'N N O = 7.2, 4.2 Hz, 2H), 7.62-7.55 (m, 2H), 7.52 (d, J
= 2.3 Hz, 1H), k4 o y ) b.) 7.40 (dd, J = 9.4, 3.3 Hz, 2H), 7.30 (dd, J = 8.7, 1.4 Hz, 1H), 6.97 .
, (d, J = 8.9 Hz, 1H), 6.78 (d, J = 6.0 Hz, 1H), 4.72-4.49 (m, 6H), a.
4.
s)) 3.70 (s, 3H), 3.55-3.42 (m, 2H), 3.09-3.01 (m, 2H), 2.60-2.54 (m, w v.
N
1H), 2.50-2.43 (m, 5H), 2.22-2.13 (m, 1H), 0.96 (d, J = 6.3 Hz, 3H).

ON 668.3 1H NMR (400 MHz, CD30D/CDC13=1/1) 8 8.61-8.56 (in, 1H), 1-54 and 1-97 olirr,,LN \
I
`-. N ---- 8.56-8.52 (m, 1H), 7.96-7.91 (in, 1H), 7.68-7.63 (in, 1H), 7.58--,.
I ..rsr o F
7.55 (in, 1H), 7.48-7.43 (in, 1H), 7.41-7.36 (m, 1H), 6.97-6.89 0 5;
y (m, 1H), 4.74-4.69 (in, 2H), 4.64-4.56 (m, 3H), 4.50-4.44 (m, :
;II
¨ 1H), 3.69 (s, 3H), 3.54-3.48 (m, 1H), 3.47-3.38 (m, 1H), 3.10- .2 CO
to CO . ) 3.00 (m, 2H), 2.87-2.76 (m, 2H), 2.63-2.53 (m, 3H), 2.51-2.41 I
N (m, 2H), 2.21-2.12 (m, 1H), 1.92-1.84 (in, 2H), 1.84-1.76 (in, 1 6 2H), 0.99-0.91 (in, 3H).

,.>"

0 4 598.3 1-134 and I-OH õis:11.r. Lc 1 r- N \ IFINMR (400 MHz, CD3013/CDC13=1/1) 8 8.56-8.51 (in, 1H), 93 7.86-7.83 (m, 1H), 7.73-7.69 (m, 1H), 7.53-7.51 (m, 1H), 7.40-tHN
N
I 'N' . N 0 7.37 (in, 1H), 6.93-6.89 (in, 1H), 5.76-5.72 (m, 1H), 4.55-4.51 (111, 1H), 4.42-4.37 (m, 1H), 4.05-4.00 (m, 2H), 3.71-3.68 (m, v n .3 2H), 3.66 (s, 3H), 3.57-3.54 (m, 2H), 3.34 (s, 3H), 3.02-2.97 (m, N-) n 2H), 2.86-2.80 (m, 2H), 2.77-2.73 (m, 2H), 2.68-2.63 (m, 2H), 1.93-1.86 (m, 2H), 1.84-1.77 (m, -.2H). 2 r.)=
r.) .

..r.:
\

c, oe c, :.-:

216 I 663.2 1-54 and 1-98 111 NMR (400 MHz, CD30D) 6 8.64-8.58 (m, 2H), 8.48 (s, 1H), 7.93-7.84 (m, 1H), 7.42-7.35 (m, 1H), 7.35-7.30 (m, 1H), 7.18-b.) o 7.14 (m, 1H), 7.01-6.95 (m, 1H), 6.88 (s, 1H), 6.74-6.69 (m, 1H), "
i..i ..
..,,..) 4.69-4.63 (m, 2H), 4.62-4.52 (m, 3H), 4.49-4.40 (m, 1H), 3.65 (s, .
ON
4.
..1 3H), 3.50-3.40 (m, 2H), 3.07-2.93 (m, 2H), 2.73-2.64 (m, 2H), w v.
2.62-2.54 (m, 2H), 2.53-2.47 (m, 1H), 2.47-2.35 (m, 2H), 2.21-N
6 2.13 (m, 1H), 1.28-1.20 (m, 6H), 0.96-0.88 (m, 3H).
o 1-162 and 1-681.2 1H NMR (400 MHz, CD30D): 6 8.72(d, J= 2.2 Hz, 1H), 8.55 (d, J = 5.1 Hz, 1H).8.01 (d, J = 2.6 Hz, 1H), 7.58 (d, J = 5.1 Hz, ----).,-..N =(...õ..,-.N 0 F
1H), 7.56-7.47 (m, 2H), 7.15 (d, J = 4.6 Hz, 1H), 7.04 (d, J = 8.9 0 :5;
) Hz, 1H), 6.70 (d, J = 6.1 Hz, 1H), 4.75-4.72 (in, 1H), 4.70-4.66 ..1"
I--CI
o (in, 2H), 4.65-4.60 (in, 2H), 4.54-4.48 (m, 1H), 3.84-3.76 (m, ig .$)(i.D.......) 1H), 3.82-2.69 (s, 3H), 3.24-3.16 (in, 1H), 2.97-2.89 (in, 1H), li N 2.82-2.69 (m, 4H), 2.66-2.48 (m, 3H), 2.03-1.89 (m, 3H), 1.88- e 6 1.77 (in, 2H), 0.94-0.86 (in, 6H).
...
o 1-162 and I-0...,N,.. µ,01-14;NLI.) 682.2 1H
NMR (400 MHz, CD30D/CDC13=111) 6 8.68-8.62 (m, 1H), \ 8.57-8.52 (m, 1H), 8.29-8.24 (m, 1H), 8.03-7.96 (m, 1H), 7.58- 94 HN'------'-i----ky" ---7.53 (m, 1H), 7.53-7.49 (m, 1H), 7.49-7.41 (m, 1H), 7.01-6.94 1 (m, 1H), 4.73-4.60 (m, 4H), 4.60-4.51 (n, 2H), 3.81-3.73 (n, v n --..
.3 1H), 3.70 (s, 3H), 3.22-3.12 (in, 1H), 2.94-2.87 (in, 1H), 2.87-n 2.80 (m, 2H), 2.77-2.68 (m, 2H), 2.67-2.57 (m, 2H), 2.55-2.43 )..) =
N (in, 1H), 2.00-1.91 (in, 3H), 1.89-1.79 (m, 2H), 0.92-0.86 (m, k.) ...
, 6 6H).

-.) c, Ge c, o.

115 I 681.2 1-166 and I-c14 -- ) J H Hz 1H)NMR (400 MHz, CD30D) 8 8.73 (d, J = 2.2 Hz, 1H), 8.55 (d, 91 - 5.1 , , 8.02 (d, J = 23 Hz 1H) ., , 7.58 (d, J = 51 Hz ., 0 :7,1 N 1 :-,r1,1 0 F b.) o 1H), 7.53 (d, J = 2.3 Hz, 1H), 7.49-7.47 (m, 1H), 7.16-7.14 (in, b.) ...),) -.
111), 7.00 (d, J = 8.8 Hz, 1H), 6.70 (d, J = 6.0 Hz, 1H), 4.70-4.50 ON
4.
..1 N (m, 6H), 3.71 (s, 3H), 3.47-3.43 (m, 1H), 3.15-3.11 (m, 2H), w v.
2.78-2.69 (m, 2H), 2.65-2.61 (m, 2H), 2.45-2.41 (m, 2H), 2.21-N
6 2.17 (m, 2H), 2.00-1.78 (m, 4H), i.08-1.04(m, 6H).
o 227 I 681.4 1H NMR (400 MHz, CD30D): 8 8.61 (s, 1H), 8.53 (d, J = 5.0 Hz, 1467 and I-HN

N
`.. 1H), 7.96-7.85 (m, 1H), 7.57 (d, J = 5.2 Hz, 1H), 7.52-7.46 (m, 91 I :**Esi 0 F
1H), 7.42-7.35(m, 1H), 7.14 (d, J = 5.7 Hz, 1H), 7.01 (d, J = 8.9 :5 .
;
Hz, 1H), 6.69 (d, J = 5.9 Hz, 1H), 4.72-4.47 (m, 6H), 3.69 (s, .:11 .
vp 3H), 3.53-3.45 (in, 1H), 3.41-3.35 (in, 1H), 3.18-3.05 (m, 2H), .2 c ,.,õ.6) 2.80-2.67 (m, 2H), 2.66-2.53 (in, 3H), 2.50-2.37 (in, 2H), 2.35- li N
6 2.27 (m, 1H), 1.98-1.88 (m, 2H), 1.87-1.77 (m, 2H), 1.73- 0:

1.59(m, 1H), 1.46-1.33 (m, 1H), 0.87-0.77 (m, 3H).
"
o v n i-3 n r.) =
r.) ....
..r.:

c, Ge c, .,:.=

Compound 68 2-(5-((5-acetyl-4,5,6,7-tetrahyd ro pyrazolo[1,5-alpyrazin-2-y1)amino)-3'-(hydroxymethyl)-1-methyl-6-oxo-1,6-dihydro-[3,41-bispyridin1-2e-y1)-7,7-dimethyl-7,8-dihydro-2H-cyclopenta[4,51pyrrolo[1,2-alpyrazin-1(611)-one i Q)1 r 1. -....-- 1 ____________________________________ o.
, b N---) H
68a Cs:

,-0Hr,---.õN \
I
I-INN ---N,, -..õ,.., 0 ___________ = i'`N
, N
N---) C) The compound 68 was prepared with compound 68a and corresponding reagents according to step 2 of intermediate 1-4 and step 2 of compound 2. [M+H] 595.3 114 NMR (400 MHz, CD30D): 6 8.55-8.50 (m, 114), 8.07-8.01 (m, 114), 7.58-7.54 (m, 1H), 7.43 (s, 1H), 7.24-7.19 (m, 1H), 6.93 (s, 1H), 6.81-6.74 (m, 1H), 5.98-5.91 (m, 1H), 4.77-4.70 (m, 2H), 4.62-4.52 (m, 1H), 4.51-4.40 (in, 1H), 4.10-4.07 (in, 1H), 4.06-3.93 (m, 3H), 3.68 (s, 3H), 2.78-2.70 (m, 2H), 2.64-2.59 (m, 2H), 2.21-2.16 (m, 3H), 1.30-1.27 (m, 6H).
Compound 69 2-(3'-(hydroxy methyl)-1-methy1-5-05-methyl-4,5,6,7-tetrahydropyrazolo[1,5-alpyrazin-2-ypamino)-6-oxo-1,6-dihydro-[3,4'-bispyridin]-2'-y1)-7,7-dimethyl-7,8-dihydro-cyclopenta[4,51pyrrolo[1,2-a]pyrazin-1(6H)-one HN =-,-c I
I) 0 .N =,...,,N 0 , ...õ.....-N ..,.
\
N N, NJ
/
68a I
=-.. I N ---HN
----------- li.- , =:.,,,;;Isi 0 \ N
N
NJ
/ ee The compound 69 was prepared with compound 68a and corresponding reagents according to step 3 of intermediate 1-2 and step 2 of compound 2. [M+1-1]' 576.2 11-1 NMR (400 MHz, CD3OD): 6 8.57-8.50 (m, 1H), 8.04-7.96 (m, 1H), 7.59-7.55 (m, 1H), 7.46-7.41 (m, 1H), 7.24-7.19 (m, 1H), 6.93 (s, 1H), 6.81-6.73 (m, 1H), 5.86 (s, 1H), 4.60-4.53 (m, 1H), 4.50-4.41 (m, 1H), 4.09-3.97 (m, 2H), 3.68 (s, 3H), 3.64-3.58 (in, 2H), 2.98-2.88 (m, 2H), 2.78-2.69 (m, 2H), 2.66-2.58 (m, 2H), 2.46 (s, 3H), 1.30-1.27 (m, 6H).
Compound 70 2-(3e-(hydroxymethy1)-5-(0-(2-methoxymethyl)-4,5,6,7-tetrahydropyrazolo(1,5-alpyrazin-2-yl)amino)-1-meth2t 1-6-o xo-1,6-dihydro-[3,4'-bispyridin1-2.-y1)-7,7-dimethyl-7,8-dihydro-2H-cyclopenta[4,51pyrrolo[1,2-alpyrazin-1(611)-one i 0....,NõI .(.,0 I
----..
-,,,.:..1... %..r L.'fq \ N, NJ
HNi 68a 0 \
I
0 N OH ,..-., ."'====" `1 ''' r--- N \
HN y-N ----\ N
N
., -...,..0 0 NJ

\ 70 The compound 70 was prepared with compound 68a and corresponding reagents according to step 2 of intermediate 1-10 and compound 2. [M+H] 611.3 114 NMR (400 MHz, CD30D): 6 8.51 (d, J = 5.1 Hz, 1H), 7.96 (d, J = 2.2 Hz, 1H), 7.54(d, J = 5.1 Hz, 1H), 7.41 (d, J = 2.2 Hz, 1H), 7.19 (d, J = 5.9 Hz, 1H), 6.92 (s, 1H), 6.76 (d, J = 5.9 Hz, 1H), 5.84 (s, 1H), 4.55 (d, J = 12.0 Hz, 1H), 4.44 (d, J = 12.0 Hz, 1H), 4.03-3.98 (m, 2H), 3.71-3.68 (m, 2H), 3.66 (s, 3H), 3.59-3.55 (m, 2H), 3.33 (s, 3H), 3.03-2.97 (m, 2H), 2.78-2.73 (m, 2H), 2.73-2.70 (m, 2H), 2.62-2.58 (m, 2H), 1.29-1.26 (m, 6H).
Compound 96 (S)-2-(3'-(hydroxymethyl)-1-methyl-5-05-(2-methylpiperazine)-1-y1)pyridin-2-y1)amino)-6-oxo-1,6-dihydro-[3,4'-bispyridini-2'-y1)-7,7-dimethy1-7,8-dihydro-2H-cyc1openta[4,5] pyrrolo[1,2-alpyrazin-1(611)-one .N
N
+ ON,N N1 0 Boc Under nitrogen, a solution of intermediate 1-168 (108 mg, 0.37 mmol), intermediate 1-99 (200 mg, .. 0.37 mmol), Pd2(dba)3 (37 mg, 0.04 mmol), Xant-phos (23 mg, 0.04 mmol) and cesium carbonate (241 mg, 0.74 mmol) in 1,4-dioxane (20 mL) was reacted at 100 C for 12 hours.
The reaction solution was concentrated in vacuum under reduced pressure, potassium carbonate (276 mg, 5.0 mmol) and methanol (10 mL) were added, and the mixture was stirred at room temperature for 15 minutes. The reaction solution was concentrated in vacuum under reduced pressure, and the resulting residue was purified with silica gel column chromatography (methanol/water) to give yellow solid (120 mg, two-step yield 42%). [M+H] 707.4.
To a solution of the yellow solid in methanol (2 mL) was added concentrated hydrochloric acid, and stirred at room temperature for 30 minutes. The reaction solution was concentrated in vacuum under reduced pressure, and the resulting residue was purified with silica gel column chromatography (methanol/dichloromethane) to give compound 96 (50 mg, yield 49%). [M+H] 607.3 11-1 NMR (400 MHz, CD3OD) 6 8.67 (d, J = 1.8 Hz, 1H), 8.53 (d, J = 5.1 Hz, 1H), 7.94 (d, J = 2.6 Hz, 1H), 7.56-7.52 (m, 2H), 7.44-7.42 (m, 1H), 7.20 (d, J = 5.9 Hz, 1H), 7.01 (d, J = 8.9 Hz, 1H), 6.92 (s, 1H), 6.77 (d, J = 5.9 Hz, 1H), 4.55-4.41 (m, 2H), 3.68 (s, 3H), 3.38-3.32 (in, 1H), 3.07-2.86 (n, 5H), 2.77-2.55 (m, 5H), 1.29-1.27 (m, 6H), 0.90 (d, J = 6.3 Hz, 3H).
The compounds in the following table were prepared with intermediate 1-99 and corresponding amine intermediates and reagents according to the preparation steps of compound 96:

Compound Structural formula LC-MS IIINMR Amine intermediate IM+Hr 103 0 N 680.3 I H NMR (400 MHz, CD30D) 8 8.51 (d, J = 5.1 Hz, 1H),Jl N I 7.63-7.48 (m, 3H), 7.39 (s, 1H), 7.21 (d, J = 5.9 Hz, 1H), F N o 7.06-7.04 (m, 111), 6.97-6.80 (m, 2H), 6.76-6.74 (in, J = 5.8, 2.5 Hz, 1H), 4.77-4.40 (m, 6H), 3.76-3.54 (m, 4H), 3.18-3.16 (m, 1H), 2.90-2.52 (m, 8H), 2.38-2.36 (m, 1H), 2.05-N
2.04 (m, 1H), 1.29-1.25 (m, 6H), 0.84 (d, J = 6.1 Hz, 3H).
123 663.2 1H NMR (400 MHz, CD30D): 8 8.84-8.78 (m, 1H), 8.55 (d, 1-170 o, NrS' = 5.1 Hz, 1H), 8.18 (d, J = 2.5 Hz, 1H), 7.66-7.54 (m, 3H), N 8 7.22 (d, J = 5.9 Hz, 1H), 7.08 (d, J = 9.0 Hz, 1H), 6.93 (s, 1H), 6.78 (d, J = 6.0 Hz, 1H), 5.12-5.03 (m, 1H), 4.88-4.85 (m, 2H), 4.83-4.77 (in, 2H), 4.64-4.56 (m, 1H), 4.51-4.44 õrir.
(m, 1H), 4.40-4.31 (mz, 1H), 4.00-3.92 (m, 1H), 3.70 (s, 3H), 3.39-3.33 (m, 1H), 2.78-2.70 (m, 2H), 2.64-2.58 (m, bo 2H), 1.29-1.25 (in, 9H).

r.) r.) 127 I 637.2 0 N OH r.: i,r.Is.... 1H NMR (400 MHz, CD30D): 8 8.75 (d, J = 2.2 Hz, 1H), 0 ..., b.) 8.56 (d, J = 5.2 Hz, 1H), 8.03 (d, J = 2.6 Hz, 1H), 7.62-7.49 o b.) ,-.
...N 0 -.
El---r-l'I'N, 1 I (m, 3H), 7.22 (d, J = 5.9 Hz, 1H), 7.04 (d, J = 8.8 Hz, 1H), C.' y 6.93 (s, 1H), 6.79 (d, J = 5.8 Hz, 1H), 4.60 (d, J = 12.0 Hz, 4.
..1 W
Vs ,=õ. NH 1H), 4.48 (d, J = 12.1 Hz, 1H), 3.70 (s, 3H), 3.51-3.45 (m, NH 2H), 3.08-2.92 (m, 4H), 2.77-2.69 (m, 2Ff), 2.63- 2.55 (m, 6 4H), 1.28-1.27 (m, 6H), 0.84 (d, J = 6.1 Hz, 3H).
o 135a I 695.3 õOAcr,;-.., N \
,..._ , E, 0 HN-.-"'''"', N ---BociNi 0 ..1 (., jN 0 .
.., N

.
No "

NJ
Commercial .

BocI...
179 I 681.4 1H NMR (400 MHz, CD30D) 8 8.64-8.58 (m, 1H), 8.51 (d, J = 5.1 Hz, 1H), 7.90 (d, J =2.7 Hz, 1H), 7.55 (d, J = 5.1 Hz, 1H), 7.48 (d, J = 2.2 Hz, 1H), 7.39-7.35 (m, 1H), 7.20 1 (d, J = 5.9 Hz, 1H), 6.98 (d, J = 9.0 Hz, 1H), 6.92 (s, 1H), -,..
mu 6.77 (d, J = 5.9 Hz, 1H), 4.61-4.54 (m, 2H), 3.99-3.97 (m, A
HN.

1)'s 14) 1H), 3.78-3.74 (m, 2H), 3.67 (s, 3H), 3.46-3.31 (m, 2H), 3.26-3.22 (m, 1H), 3.01-2.68 (m, 7H), 2.62-2.50 (m, 3H), A

"
=
OH
1.29-1.25 (m, 6H), 1.17-1.15 (m, 3H).
k.) ...

o -.) c, Ge c, ,:.-.

681.2 1H NIvIR (400 MHz, CD30D) 8 8.79-8.71 (m, 1H), 8.58-0-,..,,..õN..1 ,..0Hr....,.. N \ 0 8.53 (m, 1H), 8.37-8.28 (m, 1H), 8.05-7.99 (in, 1H), 7.60-"
o Firrk-"----N-ryN --- k4 7.56 (m, 1H), 7.56-7.52 (m, 1H), 7.51-7.46 (m, 1H), 7.26--.
,N J.õ,õ.- N
0 I-.
7.21 (m, 1H), 7.09-7.02 (m, 1H), 6.93 (s, 1H), 6.82-6.76 (m, ON
4.
..1 W
1H), 4.64-4.58 (m, 1H), 4.53-4.45 (m, 1H), 3.91-3.80 (m, en ) 4H), 3.70 (s, 3H), 3.52-3.34 (m, 41-1), 3.26-3.14 (m, 3H), NI HCOOH 3.11-3.03 (m, 1H), 2.79-2.69 (m, 2H), 2.66-2.58 (m, 2H), ri 1.30-1.27 (m, 6H), 1.01-0.93 (m, 3H).
OH OH
203 609.2 `1-1NMR (400 MHz, CD30D) 8 8.78-8.74 (m, 1H), 8.53- 1-174 ON 4 oHryi...- N \
,.. I 8.49 (m, 1H), 7.62-7.58 (m, 2H), 7.32-7.28 (m, 1I-1), 7.24- 0 7.18 (m, 2H), 6.91 (s, 1H), 6.78-6.73 (In, 1H), 4.58-4.51 (in.
.
7,,, 1 .
.
I H), 4.49-4.40 (m, 1H), 4.17-4.10 (m, 1H), 3.98-3.93 (in, sl .N 0 I..

.-c, I H), 3.77-3.73 (in, 2H), 3.70-3.65 (m, 4H), 3.62-3.55 (m, .
e) j 11-1), 3.26-3.16 (m, 1H), 2.76-2.67 (m, 2H), 2.64-2.56 (m, ,.>
.

o 2H), 1.29-1.25 (m, 6H), 1.19-1.15 (In. 3H). ir, 204 i ON .0H
664.2 1H NMR (400 MHz, CD30D) 8 8.79 (d, J = 2.3 Hz, 1H), 1-1'7 ,IL
1 8.57-8.55 (m, 1H), 7.65-7.61 (m, 21-1), 7.32-7.29 (m, 2H), HN -. 1 tcrNS 7.24-7.22 (m, 1H), 6.93-6.91 (m, 1H), 6.77 (d, J = 5.9 Hz, , N N 0 ii 1H), 4.70-4.63 (in, 6H), 4.37-4.35 (m, 1H), 3.89-3.87 (m, 'Ns N
1H), 3.71 (s, 3H), 3.48-3.46 (m, 1H), 3.36-3.34 (m, 1H), mo A
m ) 3.24-3.22 (m, 1H), 2.84-2.82 (m, 1H), 2.75-2.73 (m, 2H), A
N
2.69-2.67 (in, 11-1), 2.63-2.61 (m, 2H), 2.23-2.21 (m, 1H), 2 1.31-1.27 (m, 9H).
k..) =
"
...
o c, Ge c, ,:.-..

8.55 (d, J = 5.1 Hz, 1H), 7.68-7.58 ( 0 N 678.2 1H NMR (400 MHz, CD30D): 6 8.78 (d, J = 2.2 Hz, 1H), ortr).1.,,,,r)3 m, 2H), 7.33-7.18 (m, "
=
b4 I N 0 3H), 6.93 (s, 1H), 6.77 (d, J = 5.9 Hz, 1H), 4.72-4.45 (m, -.
,-.
C.' 6H), 4.14-4.06 (m, 1H), 4.01-3.91 (in, 1H), 3.71 (s, 3H), 4.
3.49-3.40 (m, 1H), 3.27-3.17 (m, 1H), 2.85-2.77 (m, 2H), w en '..3)14) 2.76-2.68 (m, 2H), 2.66-2.57 (m, 2H), 2.13-2.04 (m, 1H), N 2.03-1.88 (m, 2H), 1.73 -1.56 (m, 1H), 1.30-1.27 (m, 6H), 0.89 (t, J = 7.4 Hz, 3H).
o 222 I 650.2 0 N- _.-...E-1HNMR (400 MHz, CD3OD/CDC13=1/1) 6 8.82-8.76 (m, -'-.,--- 1- -- OH iiirNS
HNN --- 111), 8.57-8.50 (m, 1H), 7.69-7.63 (m, 1H), 7.63-7.57 (m, 0 '7-LN =#1.i 1H), 7.27-7.20 (m, 2H), 7.16-7.10 (m, 1H), 6.95 (s, 1H), " sl I--.I I

vz 6.75-6.68 (m, 1H), 4.73-4.69 (m, 2H), 4.66-4.61 (m, 2H), " -,I
N N
ro C ) 4.57-4.51 (m, 1H), 4.46-4.45 (m, 1H), 3.71 (s, 3H), 3.57- .
N 3.49 (m, 5H), 2.77-2.67 (m, 2H), 2.65-2.57 (m, 2H), 2.52-6 2.42 (m, 4H), 1.30-1.26 (m, 6H). ...
o 229 I 634.3 0..,...N., ,,OHic...N \
Ili NMR (400 MHz, CDC13) 6 8.63 (s, IF!), 8.54 (d, J = 5.1 Hz, 1H), 7.91-7.74 (m, 3H), 7.47 (d, J = 5.0 Hz, 1H), 7.24-N ---..,...61õ,N 0 7.22 (m, 1H), 7.01 (s, 1H), 6.90 (d, J = 6.5 Hz, 1H),6.78 (d, mo -)) J = 8.9 Hz, 1H), 6.63 (d, J = 5.9 Hz, 1H), 5.08 (d, J- 11.3 A
1 - i Hz, 1H), 4.53-4.43 (m, 5H), 4.36-4.32 (m, 1H), 3.70 (s, 3H), A

'5 3.03-2.90 (m, 4H), 2.72-2.57 (m, 4H), 2.03-1.94 (m, 4H), 1.30-1.26 (s, 611).
k..) =
k..) ...
..=
o -4 c, Ge c, ,:.-.

230 661.2 `1-1 NMR (400 MHz, CD30D) 8 8.57-8.50(m, 1H), 8.46- 1-179 0 4 1 OHic6 8.40 (m, 1H), 7.66-7.60 (m, 1H), 7.60-7.55 (m, 1H), 7.49-0b.) =-s, N
---- p % I Nst*1 0 7.43 (m, 1H), 7.24-7.19 (m, 1H), 7.09-7.02 (m, 1H), 7.03- k4 ,-.
-.
6.96 (m, 1H), 6.93 (s, 1H), 6.80-6.74 (m, 1H), 4.69-4.63 (m, C.' 4.
2H), 4.62-4.55 (m, 1H), 4.52-4.44 (m, 2H), 4.41-4.36 (m, w 111), 4.31 (s, 1H), 3.98-3.86 (m, 1H), 3.69 (s, 3H), 3.54 (s, ,., ')(s) N ''H 111), 3.44-3.38 (m, 1H), 3.09-2.97 (m, 1H), 2.86-2.78 (m, 6 2H), 2.76-2.69 (m, 2H), 2.65-2.58 (m, 2H), 1.98-1.83 (m, o 2H), 1.29-1.27 (m, 6H).
231 1 675.3 ON
11-1 NIVIR (400 MHz, CD30D) 8 8.57-8.53 (m, 2H), 8.01 (d, HN - µ-= N

w I J = 2.9 Hz, 1H), 7.58 (d, J = 5.1 Hz, 1H), 7.49 (d, J = 2.3 , N 0 1.1 INJI
O
i-i NO I Hz, 1H), 7.40-7.36 (m, 1H), 7.22 (d, J = 5.9 Hz, 1H), 7.00-ce 6.90 (m, 2H), 6.77 (d, J = 5.8 Hz, 1H), 4.64-4.45 (m, 6H), in(Nj 3.74-3.61 (m, 5H), 3.43-3.41 (m, 1H), 2.79-2.57 (m, 4H), .
N
2.51-2.13 (m, 4H), 1.30-1.26 (m, 6H), 0.94-0.72 (m, 4H). z o 232 I O.,,..N 0H 649.4 'H -INm.tt- (400 MHz, CD30D) 8 8.65-8.60 (m, 1H), 8.57-,.,.. ..,eN,N \
8.51 (m, 1H), 7.93-7.86 (m, 1H), 7.60-7.55 (m, 11-1), 7.53-HN,('N.I'-'''N ---7.46 (m, 1H), 7.41-7.35 (m, 1H), 7.24-7.18 (m, 1H), 7.03-mo 4....t...., .N :õ,,...,N
0 n 6.96 (m, 1H), 6.93 (s, 1H), 6.82-6.75 (m, 1H), 4.63-4.56 (m, ..., 1H), 4.51-4.44 (m, 1H), 3.87-3.81 (m, 1H), 3.79-3.74 (m, n N.,..
t.) 1H), 3.69 (s, 3H), 3.68-3.62 (m, 1H), 3.51-3.44 (in, 1H), k.) ( _..ões) ...
3.35-3.32 (m, III), 3.29-3.24 (m, 1H), 2.91-2.81 (m, 2H), , NC, jlo '7:1-c, 2.78-2.69 (In, 31-1), 2.66-2.58 (m, 2H), 2.50-2.33 (m, 4H), =
C.' ,:.-.

1.30-1.27 (m, 6H).

b.) 233 o- 648.4 1H NMR (400 MHz, CD30D) 6 8.65 (d, .1= 2.2 Hz, 1H), 1-182 =
_ )..) i... ====.. -- r iv--1.
--0 H rci:4131 i...
8.61-8.55 (m, 1H), 7.99-7.92 (m, 1H), 7.66-7.58 (m, 1H), -.
ON
4.
HN"----..k''''.Nr=r=- N ---- 7.54 (d, J = 2.2 Hz, 1H), 7.47-7.39 (m, 1H), 7.30-7.22 (m, w 1H), 7.07-7.01 (m, 1H), 6.97 (s, 1H), 6.86-6.78 (m, 1H), en =-.-1õ9 4.64 (d, J = 12.0 Hz, 1H), 4.52 (d, J = 12.0Hz, 1H), 3.99-N
.., =,. 3.83 (m, 2H), 3.73 (s, 3H), 3.62-3.60 (m, 2H), 3.18-3.01 (m, 64H), 2.83-2.57 (m, 4H), 1.88-1.83 (m, 2H), 1.81-1.74 (m, 4H), 1.34-1.31 (m, 6H).
234 677.4 ON 0 11-1 NMR. (400 MHz, CD30D) 6 8.58 (d, J = 2.3 Hz, 1H), I HNr2I-S
?, HN 8.51 (d, J = 5.1 Hz, 1H), 7.82 (d, J = 2.7 Hz, 1H), 7.55 (d, J .., ...
-..
,..:. I
, N 0 = 5.1 Hz, 1H), 7.47 (d, J = 2.2 Hz, 1H), 7.33-7.29 (m, 1H), ...
,..:.
-,14 .

..
7.18 (d, J = 5.9 Hz, 1H), 6.98 (d, J = 9.0 Hz, 1H), 6.92 (s, .
..
0 ) 1H), 6.76 (d, J =
5.9 Hz, 111), 4.74-4.43 (m, 6H), 3.74-3.53 (m, 5H), 3.16-3.00 (m, 2H), 2.78-2.47 (m, 6H), 2.10-2.06 (m, 1H), 1.29-1.25 (m, 6H), 0.92-0.88 (in, 6H).
o mo A
i-i A

k.) =
k=.) ..

c, Ge c, 4.-..

..
235 661.3 1-1g4 oy.,r!isi. --OH

11-1 NM R (400 MHz, CD30D) 5 8.58-8.49 (m, 2H), 7.61-O"
Hrr"------ry-N --k..) 7.52 (m, 2H), 7.50-7.45 (m, IH), 7.24-7.18 (m, 1H), 7.03-,-.
-1...õ..;.N 0 I-.
-.
I 6.94 (m, 2H), 6.92 (s, 1H), 6.80-6.74 (m, 1H), 4.61-4.41 (m. ON
4.
'`..
..1 6H), 4.34-4.24 (m, 2H), 3.75-3.67 (in, 4H), 3.20-3.15 (m, w en K >N
L.--) 2H), 2.96-2.83 (m, 2H), 2.78-2.68 (m, 2H), 2.68-2.56 (m, N 3H), 2.10-2.02 (m, IH), 1.29-1.27 (m, 6H).

7.76 (m, 1H), 7.61-7.54 (m, 1H), 7.52-7.44 (m, 1H), 7.36-0 ,t! 1 OHNr... N......\ 663.3 iH NMR (400 MHz, CD30D) 5 8.62-8.46 (m, 2H), 7.86-HN
1 ...:t1 o 7.28 (m, 1H), 7.25-2.17 (m, 1H), 7.06-6.96(m, 11-1), 6.96- .
,., el) ...
-.I
6.87 (m, 1H), 6.83-6.71 (m, 1H), 4.62-4.57 (m, 1H), 4.52-'8 ...
o .
o 4.44 (m, 1H), 4.02'-3.91 (m, 1H), 3.85-3.66 (m, 6H), 3.38- .
.
ils) 3.33 (m, 1H), 3.09-2.97 (m, 1H), 2.76-2.53 (m, 8H), 2.35- .
.

zõ...,..0 2.18 (m, 211), 1.28 (s, 611), 1.09 (s, 311).
.
...
mo A
i-i A

k.) =
k=.) ..

o Ge o 4.-..

Compound 98 2-(5-amino-Y-(hydroxymethyl)-1-methy1-6-oxo-1,6-dihydro-I3,4'-bispyridin1-2'-y1)-7,7-dimethy1-7,8-dihydro-2H-cyclopenta[4,5]pyrrolo[1,2-alpyrazin-1(61-h-one I
_______0 i OH ,..-0ArN \ 0,..,.,..,..N -I --0 H r=-'''' `N \
N''''''''==---"Thr + ' c:jI
I H0'lakC:21N -- .
I H2N -µ-' , '"-- N --Under nitrogen, a solution of intermediate 1-148 (220 mg, 0.60 mmol), intermediate 1-4 (237 mg, 0.60 mmol), Pd(dppf)C12CH2C12 (49 mg, 0.06 mmol), Xphos(57 mg, 0.12 mmol) and potassium phosphate trihydrate (479 mg, 1.80 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was reacted at 100 C for 4 hours. The reaction solution was concentrated in vacuum under reduced pressure, and the resulting residue was purified with silica gel column chromatography (methanol/water) to give yellow solid (268 mg, yield 70%). [M+Hr 638.3.
To a solution of the yellow solid in methanol (5 mL) was added trifluoroacetic acid (2 mL), and stirred at room temperature for 2 hours. The reaction solution was concentrated in vacuum under reduced pressure, and potassium carbonate (174 mg, 1.26 mmol) and methanol (5 mL) were added to the resulting residue, and the mixture was stirred at room temperature for 15 minutes. The reaction solution was concentrated in vacuum under reduced pressure, and purified with silica gel column chromatography (methanol/water) to give compound 98 (48 mg, yield 26%). [M+H] 432.2 1HNMR (400 MHz, CD30D) 8 8.55-8.48 (m, 1H), 7.52-7.48 (m, 1H), 7.36-7.30 (m, 1H), 7.24-7.20 (m, 1H), 6.95-6.91 (m, 1H), 6.91-6.86 (m, 1H), 6.78-6.72 (m, 1H), 4.55-4.49 (m, 1H), 4.47-4.41 (m, 1H), 3.64 (s, 3H), 2.79-2.68 (m, 2H), 2.66-2.56 (m, 2H), 1.30-1.27 (m, 6H).
Compounds 119 and 120 2-(Y-(hydroxymethyl)-54(5-(2-methoxyethyl)-4-methyl-4,5,6,7-tetrahydropyrazololl,5-a] pyrazin-2-y1) amido)-1-methy1-6-oxo-1,6-dihydro-I3,4'-bispyridinl-21-y1)-7,7-di methyl-7,8-dihydro-2H-cyclopenta[4,51pyrrolo[1,2-d][1,2,41triazin-1(611)-one optically pure enantiomer I

HN N% , I ¨ f ,iii- , NI \ =
I
--ky = HN ' -- N ,.,,, ..-6 .. 0 Resolution `N -,-.N %., µAN N 0 + \ ' N ii¨N
KO) - ,====(0!) N N-=-, N
/
K ' ) \
ol , 0 d \ \ \
110 119 & 120 (RS)-2-(3'-(hydroxymethyl)-5-05-(2-methoxyethyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yDamido)-1-methyl-6-ox o-1,6-dihydro-[3,4'-bispyri di fl]-2'-y1)-7,7-dimethy1-7,8-dihydro-21/-cyclopenta[4,5]pyrrolo[1,2-4[1,2,4]triazin-1(610-one (compound 110, 110 mg) was resolved by chiral HPLC to give a pair of optically pure enantiomers, (R)-2-(3'-(hydroxymethyl)-5-05-(2-methoxyethyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amido)-1-methy1-6-oxo-1,6-dihydro-[3,4'-bispyridin]-2'-y1)-7,7-dimethy1-7,8-dihydro-2H-cyclopenta[4,5]pyrrolo[1,2-4[1,2,4]triazin-1(610-one and (S)-2-(3'-(hydroxymethyl)-54(5-(2-methoxyethyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a] pyrazin-2-yl)ami do)-1-methy1-6-oxo-1,6-dihydro-[3,4'-bispyri din]-2'-yI)-7,7-di m ethy1-7,8-dihydro-2/1-cyclopenta[4,5]pyrrolo[1,2-4[1,2,4]triazin-1(611)-one. Chiral HPLC
resolution conditions: column: AD-H (0.46 cm I.D. x 15 cm L); Mobile phase: CO2/ethanol =
60:40; Flow rate: 2.5 mL; Detector wavelength: UV 254 nm).
Under the above conditions, the compound obtained after removing the solvent from the first eluent obtained was named compound 119 (40 mg, yield 36%,), ee% = 100%, MS (m/z):
626.3[M+Hr. IFINMR (400 MHz, CD30D) 8 8.57-8.51 (m, 1H), 8.43-8.38 (m, 1H), 7.97-7.91 (m, 1H), 7.60-7.57 (m, 1H), 7.41-7.38 (m, 1H), 7.07-7.01 (m, 1H), 5.93-5.89 (in, 1H), 4.60-4.51 (m, 2H), 4.04-3.91 (m, 2H), 3.83-3.76 (m, 1H), 3.68 (s, 3H), 3.60-3.53 (m, 2H), 3.40-3.35 (m, 1H), 2.99-2.87 (m, 2H), 2.86-2.81 (m, 2H), 2.73-2.62 (in, 3H), 1.43-1.39 (m, 3H), 1.31 (s, 6H).
Under the above conditions, the compound obtained after removing the solvent from the second eluent obtained was named compound 120 (42 mg, yield 38%,), ee% =
99.68%, MS
(m/z): 626.3[M+Hr. NMR (400 MHz, CD30D) 8 8.56-8.52 (m, 1H), 8.42-8.38 (m, 1H), 7.95-7.92 (m, 1H), 7.60-7.57 (m, 1H), 7.41-7.38 (m, 1H), 7.06-7.02 (in, 1H), 5.93-5.89 (m, 1H), 4.60-4.49 (m, 2H), 4.03-3.93 (m, 2H), 3.82-3.76 (in, 1H), 3.68 (s, 3H), 3.59-3.52 (m, 2H), 3.40-3.34 (in, 1H), 2.99-2.87 (m, 2H), 2.86-2.81 (s, 2H), 2.73-2.62 (m, 3H), 1.43-1.39 (m, 3H), 1.30 (s, 6H).
-Compound Structural formula LCMS 1H NMR
Original [M+Hr compound NMR (400 MHz, CD30D) 8 8.53 (d, J
= 5.1 Hz, 1H), 7.97-7.95 (m, 1H), 7.56 (d, o J = 5.1 Hz, 1H), 7.42 (d, J = 2.2 Hz, 1H), =
7.21 (d, J = 5.9 Hz, 1H), 6.92 (s, 1H), 6.76 HN N --116 625.3 (d, J = 5.9 Hz, 1H), 5.90 (s, 1H), 4.60-4.39 (m, 2H), 4.01-3.97 (m, 2H), 3.79 (q, J
6.6 Hz, 1H), 3.67 (s, 3H), 3.61-3.52 (m, 2H), 3.39-3.32 (m, 4H), 2.94-2.90 (m, 2H), 2.79-2.53 (in, 5H), 1.40 (d, J = 6.5 Hz, 3H), 1.30-1.26 (m, 6H).

1H NMR (400 MHz, CD30D) 8 8.52 (d, J
= 5.1 Hz, 1H), 7.97-7.95 (m, 1H), 7.56 (d, J = 5.1 Hz, 1H), 7.41 (d, J = 2.1 Hz, 1H), 7.21 (d, J = 5.9 Hz, 1H), 6.92 (s, 1H), 6.76 117 625 3 (d, J = 5.9 Hz, 1H), 5.90 (s, 1H), 4.62-4.39 .
(m, 2H), 4.06-3.89 (m, 2H), 3.78 (q, J =
O I OH
6.6 Hz, 1H), 3.67 (s, 3H), 3.60-3.48 (m, HN "=- 1:".1"1 N 2H), 3.42-3.32 (m, 4H), 3.00-2.84 (m, 2H), 2.79-2.54 (m, 5H), 1.40 (d, J = 6.5 Hz, 3H), 1.30-1.26 (m, 6H).
O 4 NMR (400 MHz, CD30D) 8 8.50 (d, J
Tar.ty- = 5.1 Hz, 1H), 7.97 (t, J = 2.4 Hz, 1H), HN y o ^ N 7.53 (d, J = 5.1 Hz, 1H), 7.40 (d, J = 2.2 4:11 Hz, 1H), 7.19 (d, J = 6.4 Hz, 1H), 6.91 (s, 136 623.2 1H), 6.75 (d, J = 5.8 Hz, 1H), 5.88 (s, 1H), 4.72-4.39 (m, 6H), 4.03-3.90 (m, 3H), 3.78-3.76 (m, 1H), 3.65 (s, 3H), 3.19-3.08 (m, 1H), 2.84-2.51 (m, 5H), 1.28-1.24 (m, 9H).

H NMR (400 MHz, CD30D) 8 8.53 (d, J
= 5.2 Hz, 1H), 8.02-7.96 (m, 1H), 7.57 (d, J = 5.1 Hz, 1H), 7.41 (d, J = 6.4 Hz, 1H), 137 OyN.. OHiNçJ623 2 7.25-7.18 (in, 1H), 6.92 (s, 1H), 6.76 (d, J
.
,= 5.9 Hz, 1H), 5.90 (s, 1H), 4.70-4.48 (m, 6H), 4.05-3.95 (m, 3H), 3.83-3.79 (m, 1H), 3.68 (s, 3H), 3.21-3.17 (m, 1H), 2.84-2.60 (m, 5H), 1.32-1.24 (m, 9H).
NMR (400 MHz, CD30D): 8 8.69 (t, J
= 2.4 Hz, 1H), 8.56 (dd, J = 5.1, 1.2 Hz, HO 1H), 7.97 (d, J = 2.5 Hz, 1H), 7.59 (d, J =
O 4 OH 5.1 Hz, 1H), 7.55-7.51 (m, 1H), 7.47 (dd, HN
= 8.9, 2.8 Hz, 1H), 7.39 (d, J = 6.0 Hz, '1r 1H), 7.04 (d, J = 8.9 Hz, 1H), 6.91 (s, 1H), 198 679.3 6.83 (dd, J = 5.9, 2.1 Hz, 1H), 4.76-4.46 (m, 7H), 3.78-3.63(m, 4H), 3.55-3.44 (m, 1H), 3.17-3.07 (m, 2H), 2.92-2.55 (m, 4H), 2.54-2.46 (m, 1H), 2.44-2.25 (m, 1H), 1.23-1.17 (m, 611), 0.97 (d, J = 6.3 Hz, 3H).

1H NMR (400 MHz, CD30D): ö 8.67 (t, J
= 2.1 Hz, 1H), 8.55 (dd, J = 5.1, 1.7 Hz, 1H), 7.95 (d, J = 2.7 Hz, 1H), 7.59 (d, J =
5.2 Hz, 1H), 7.51 (dd, J = 3.8, 2.3 Hz, 1H), 7.44 (dd, J = 8.9, 2.9 Hz, 1H), 7.39 199 679.3 (d, J = 5.9 Hz, 1H), 7.03 (d, J =
8.9 Hz, 1H), 6.91 (s, 1H), 6.83 (dd, J = 5.9, 2.1 HO
= (F8 Hz, 1H), 4.77-4.46 (m, 7H), 3.76-3.65 (m, 3H), 3.56 -3.44 (m, 2H), 3.13-3.00 (m, N 0 2H), 2.76-2.39 (m, 5H), 2.26-2.14 (m, 1H), 1.24-1.18 (m, 6H), 0.97 (d, J = 6.3 ) Hz, 3H).
The optically pure enantiomeriediastereomeric compounds in the above table were obtained by chiral HPLC resolution. The resolution conditions were: flow rate:
2.5 m1_, detector wavelength: UV 254 nm; the chiral column and mobile phase used, and the ee(de) values of the obtained compounds were shown in the table below (wherein in each pair of enantiometic compounds, the earlier numbered compounds were the compounds obtained after removing the solvent from the first eluent obtained from the chiral column, and the later numbered compounds were the compounds obtained after removing the solvent from the second eluent obtained from the chiral column):
Compound Column Mobile phase ee(de)%
116 AD-H (0.46 cm COilethanol (0.1%DEA) ¨ 100%
117 I.D. x 15 cm L) 60:40 99.76%
136 AS-H (0.46 cm CO2/isopropyl alcohol 100%
137 1.D. x 15 cm L) (0.1%DEA) = 60:40 98.50%
198 AD-H (0.46 cm CO2/isopropyl alcohol 99.38%
199 I.D. x 15 cm L) (0.1%DEA) = 50:50 98.42%
Compound 135 24(2'-(7,7-dimethyl-1-oxo-1,6,7,8-tetrahydro-2H-cyclopenta14,51pyrroloi1,2-alpyrazin-2-y1)-3'-(hydroxymethyl)-1-methyl-6-oxo-1,6-dihydro-I3,4'-bispyridinl-5-y1)amino)-6,7-dihydropyrazolo 11,5-a] pyrazin-5(41/)-nitrile jyN 0HcNiSsi-I I N
N HN I'N.

N) NJ
Boo To a solution of compound 135a (250 mg, 0.36 mmol) in methanol (5 mL) was added concentrated hydrochloric acid (2 mL), and stirred at 50 C for 30 minutes. The reaction solution was concentrated in vacuum under reduced pressure, acetonitrile (20 mL), potassium carbonate (150 mg, 1.08 mmol) and cyanogen bromide (45 mg, 0.43 mmol) were added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into water, and extracted with dichloromethane, the organic phase was collected, and concentrated in vacuum under reduced pressure, and the resulting residue was purified with silica gel column chromatography (methanol/water) to give compound 135 (60 mg, yield 29%).
[M+H] 578.3 1H NMR (400 MHz, CD30D) 8 8.49 (d, J = 5.1 Hz, 1H), 8.05 (d, J = 1.8 Hz, 1H), 7.51 (d, J =
7.2 Hz, 1H), 7.41 (d, J = 1.8 Hz, 1H), 7.18 (d, J = 5.9 Hz, 1H), 6.90 (s, 1H), 6.75 (d, J = 5.9 Hz, 1H), 5.89 (s, 1H), 4.57-4.37 (m, 4H), 4.10 (t, J = 5.3 Hz, 2H), 3.77-3.58 (m, 5H), 2.78-2.53 (m, 4H), 1.28-1.24 (m, 6H).
The compounds in the following table were prepared with corresponding intermediates and reagents according to the preparation steps of compound 135:
Compound Structural formula LC-MS IHNMR
Intermediate 1M+111+
142 0 4, OH N/ JTh 550.2 I H NMR (400 MHz, 1-187 and 1-cD3oDicDa3=1/2) 8 8.60- 129 8.56 (m, 1H), 8.05-8.01 (m, ..) 1H), 7.62-7.61 (m, 1H), 7.56-/
7.53 (m, 1H), 7.10-7.06 (m, 1H), 7.06-7.03 (m, 1H), 6.71-6.65 (m, 1H), 5.94-5.88 (m, 1H), 4.54-4.52 (m, 2H), 4.45-4.41 (m, 2H), 4.25-4.17 (m, 2H), 3.78-3.72 (m, 5H), 2.95-2.89 (m, 2H), 2.86-2.80 (m, 2H), 2.64-2.55 (m, 2H).
143 4 579.3 1H NMR (400 MHz, 1-187 and 1-ccX,),6 111#''N.,`
/, \ p CD30D/CDC13=2/1) 8 8.60- 114 N 0 ..,, ...
8.55 (m, 1H), 8.34-8.31 (m, 1H), 8.06-8.02 (m, 1H), 7.59-N 7.56 (m, 1H), 7.48-7.45 (m, 1H), 7.11-7.08 (m, 1H), 5.98-5.93 (m, 1H), 4.58-4.52 (m, 4H), 4.21-4.16 (in, 2H), 3.78-3.74 (m, 2H), 3.72 (s, 3H), 2.86-2.84 (m, 2H), 2.69-2.65 (m, 2H), 1.34 (s, 6H).
Compound 223 (S)-2-(3'-(methoxymethyl)-1-methyl-5-(methyl(5-(2-methyl-4-(oxetan-3-y1)piperazin-1-y1)pyridin-2-Aamino)-6-oxo-1,6-dihydro-13,4'-bispyridin1-2'-y1)-7,7-dimethyl-7,8-dihydro-2H-cyclopenta[4,51pyrrolo[1,2-alpyrazin-1(6H)-one 0 N ,..0 HN N

At 0-5 C, to a solution of compound 19(100 mg, 0.15 mmol) in DMF(10 mL) was added 60% NaH (38 mg, 0.95 mmol), and stirred at this temperature for 30 minutes.
Iodomethane (123 mg, 0.87 mmol) was further added, and the reaction solution was reacted at room temperature for 30 minutes. The reaction solution was poured into water, and extracted with ethyl acetate, the organic phase was collected, and concentrated in vacuum under reduced pressure, and the resulting residue was purified with silica gel column chromatography (methanol/water) to give compound 223 (18 mg, yield 7%). [M+HI6 691.2.
NMR (400 MHz, CD30D) 6 8.61-8.54 (m, 1H), 7.96-7.89 (m, 1H), 7.85-7.79 (m, 1H), 7.78-7.71 (m, 1H), 7.62-7.56 (m, 1H), 7.47-7.39 (m, 1H), 7.24-7.17 (In, 1H), 6.91 (s, 1H), 6.77-6.66 (m, 2H), 4.72-4.67 (in, 2H), 4.64-4.58 (m, 3H), 4.42-4.35 (m, 1H), 4.27-4.19 (in, 1H), 3.68 (s, 3H), 3.54-3.47 (m, 1H), 3.34 (s, 3H), 3.14 (s, 3H), 3.07-2.96 (m, 2H), 2.78-2.71 (in, 2H), 2.67-2.59 (m, 3H), 2.59-2.51 (m, 1H), 2.43-2.34 (m, 1H), 2.14-2.05 (m, 1H), 1.29 (s, 6H), 0.93-0.90 (m, 3H).
Compound 228 N
N HN

At 0-5 C, to a solution of compound 19(200 fig, 0.30 mmol) in DMF(10 mL) was added 60% NaH (38 mg, 0.95 mmol), and stirred at this temperature for 30 minutes.
Iodomethane (111 mg, 0.78 mmol) was further added, and the reaction solution was reacted at room temperature for 30 minutes. The reaction solution was poured into water, and extracted with ethyl acetate, the organic phase was collected, and concentrated in vacuum under reduced pressure, and the resulting residue was purified with silica gel column chromatography (methanol/water) to give compound 228 (45 mg, yield 9%). [M+HI6 677.3.
NMR (400 MHz, CD30D) 6 8.74-8.68 (m, 1H), 8.55-8.49 (m, 1H), 7.98-7.89 (m, 1H), 7.57-7.51 (m, 1H), 7.43-7.39 (m, 1H), 7.37-7.32 (m, 1H), 7.22-7.14 (m, 1H), 7.01-6.95 (m, 1H), 6.91 (s, 1H), 6.79-6.71 (m, 1H), 4.70-4.65 (m, 2H), 4.63-4.55 (m, 2H), 4.42-4.34 (m, 1H), 4.28-4.21 (in, 1H), 3.68 (s, 3H), 3.51-3.44 (m, 2H), 3.11 (s, 3H), 3.09-2.98 (m, 2H), 2.76-2.69 (in, 2H), 2.63-2.58 (m, 2H), 2.56-2.50 (m, 1H), 2.49-2.38 (m, 2H), 2.23-2.15 (m, 1H), 1.27 (s, 6H), 0.97-0.91 (m, 3H).
Example 2 Determination of Biochemical BTK
1. Reagents and materials BTK recombinant protein: Invitrogen, Cat# PV3363;
T-LYTE kinase test kit-tyrosine 1 peptide: Invitrogen, Cat# PV3190;
384-well low-flange black flat-bottomed polystyrene NBS microplate, no lid, no sterilization: Corning, Cat# 3575;
96-well polystyrene conical-bottomed MicroWellTM plate, sealed with a lid:
Thermo ScientificTM NuncTM, Cat# 277143;
Envision multi-mode plate reader: PerkinElmer;
Mixmate shaker: Eppendorf;
TS-2102 shaking incubator: TENSUC;
2. Methods T-LYTE biochemical assay employs a fluorescence resonance energy transfer (FRET) -based, coupled-enzyme format and is based on the differential sensitivity of phosphorylated and non-phosphorylated peptides to proteolytic cleavage. Both ends of the short peptide substrate are labeled with two fluorescent groups to form a FRET paired combination. In the primary reaction (the Kinase Reaction), the kinase transfers the y-phosphate of ATP to a single serine or threonine residue on the short peptide substrate. In the secondary reaction (the development reaction), the non-phosphorylated short peptides were recognized and cleaved by a site-specific protease (the development reagent). Phosphorylated short peptides can resist such cleavage.
Cleavage of short peptides can disrupt the donor (such as coumarin) and receptor fluorophores (fluorescein) on the short peptides, while the phosphorylated short peptides can maintain FRET. The calculation method of the ratio is as follows, and the ratio of the respective emission signals generated by the donor fluorophores emitted (after excitation at 400 nm) to the receptors is calculated. Emission signal ratio = emitted light by coumarin (445 nm)lemitted light by fluorescein (520 run). If the FRET short peptide is phosphorylated (such as no kinase inhibitor), the emitted light ratio will remain in a lower level. If the FRET short peptide is non-phosphorylated (such as kinase inhibitor), the emitted light ratio will be in a higher level. In this way, the inhibitory effects of different compound inhibitors on BTK kinase activity would be distinguished.
The experiment were carried out according to the instructions of the E-LYTE
kinase test kit-tyrosine 1 peptide. Reagent preparation: 1.33 x kinase buffer: 5 x kinase buffer was diluted with water to 1.33 x kinase buffer; an enzyme solution: the kinase was dissolved in 1.33 x kinase buffer with the final working concentration being 3.32 nM; a short peptide solution: a short peptide stock solution (1 mM dissolved in DMSO) was dissolved in 1.33 x kinase buffer with the final working concentration being 2 Z'-LYTE Tyr01 phosphorylated short peptide solution, 0.6 pi of stock solution (1 mM dissolved in DMSO) was dissolved in 149.4 1 of 1.33 x kinase buffer; an ATP solution: an ATP stock solution (10 mM aqueous solution) was dissolved in 1.33 x kinase buffer with the fmal working concentration being 32 pM; a color-developing solution:
color-developing solution B was dissolved in color-developing buffer with the final working concentration being 1 x color-developing solution; 4 x compound preparation:
the compound was diluted in 3-fold gradient concentration to finally obtain 4% DMSO aqueous solution containing different concentrations of the compound, with the final working concentration being 3000, 1000, 333.33, 111.11, 37.04, 12.35, 4.12, 1.37 nM, 8 concentration points in total.
Specific steps of the experiment: In the experiment, there were three control groups, each with 8 replicate wells, which were Cl 100% inhibition group (no ATP), C2 0%
inhibition group (with ATP), and C3 100% phosphorylation group, respectively. 2.5 ill of serially diluted compound was added to each well of a 384-well plate, with double replicate wells, and 4%
DMSO solution was added to wells Cl, C2, and C3. After that, except for wells C3, 2.5 pi of BTK enzyme solution was added to each remaining well, which was left to stand at 4 C for 30 minutes. After that, except for wells C3, 2.5 p,1 of short peptide solution was added to each well, and 5 pl of phosphorylated short peptide solution was added to each of wells C3. 2.5 p,1 of 1.33x kinase buffer was added to each of wells Cl and C3, and 2.5 pl of ATP solution was added to each of the remaining wells. The wells were centrifuged transiently, and the plate was shaken at 1000 rpm for 30 seconds to perform transient centrifuge. The 384-well plate was placed in a shaking incubator protected from light and incubated at room temperature for 1 hour. After the enzymatic reaction was completed, 5 p,1 of development solution was added to each well, which was centrifuged transiently, and the plate was shaken at 1000 rpm for 30 seconds to perform transient centrifuge. The 384-well plate was placed in a shaking incubator protected from light and incubated at room temperature for 1 hour until the color-developing reaction was completed.
3. Detection After the development reaction was completed, the 384-well plate was taken out to perform plate reading using the Envision multi-mode plate reader, and the optical signal was detected at the emission wavelength of 405 nm and the excitation wavelength of 460 nm/535 nm.
The reading value at 460 nm/535 nm of each well was used as the signal value of each well.
4. Calculation The average signal value of C3 was regarded as 100% phosphorylation, the average signal value of Cl was regarded as 0% phosphorylation, and the average signal value of C2 was used to calculate the phosphorylation ratio of short peptides in the presence of BTK
kinase. According to the signal value in each well, the inhibition ratio (%) of each concentration of compounds was calculated, and the 205 model in XL-Fit 5.3 software (ID Business Solutions Limited) was used to obtain an IC50 value.
The phosphorylation ratio is calculated as follows:

Phosphorylation ratio (%) = 100-100 x [(emission signal ratio x Fl00%)-Cioo4{
(Co% -C100%) + [emission signal ratio x (Floc& - Foiy)]}
wherein, the emission signal ratio = coumarin emission signal (460 nm)/fluorescein emission signal (535 nm); C10004= average value of coumarin emission signal in C3; Co%=
average value of coumarin emission signal in Cl; F100% = average value of fluorescein emission signal in C3; Fo%= average value of fluorescein emission signal in Cl.
The inhibition ratio is calculated as follows:
Inhibition ratio (%) = 100 x (phosphorylation ratio in C2 - phosphorylation ratio in testing well)/phosphorylation ratio in C2 5. Test results , Compound IC50 a Compound IC50 Compound ICso Compound IC50 No. (1M) No. (AM) No. (uM) No.
(PM) ..... 1 0.035 21 0 - .008 42 0.269 61 0.004 2 0.009 22 0.010 43 ' 0.009 62 ' 0.021 3 0.224 23 0.044 44 0.022 63 0.008 4 0.756 :24 ' 0.003 45 0.011 64 0.020 .._ 5 0.009 25 - 0.008 = -46 0.008 65 0.014 6 0.002 ' 26 0.007 47 0.003 66 0.011 7 <0.001 27 0.007 48 0.004 67 ' 0.082 8 0.012 1 28 0.003 49 0.006 68 0.005 , 9 <0.001 29 0.008 50 ' 0.024 69 0.007 ....._ 10 0.018 30 0.009 51 0.01 70 0.010 11 0.106 31 0.009 52 0.018 71 0.006 13 - 32 0.017 ' 53 0.033 72 0.058 ' 14 0.051 33 0.025 54 . 0.015 73 0.216 0.017 34 0.005 55 0.019 74 0.017 16 - 35 0.017 56 0.020 75 ' 0.011 17 - 36 0.031 57 0.006 76 0.123 18 0.004 37 0.132 58 0.008 77 0.441 19 0.008 40 > 3 59 0.005 78 0.008 ' 0.027 41 0.012 60 0.004 79 .
<0.001 ' 80 0.005 12 0.230 38 <0.001 39 0.024 81 0.008 120 0.008 159 0.006 198 0.004 82 0.006 121 0.023 160 0.003 199 0.008 83 0.013 122 <0.001 161 0.004 200 0.004 84 0.009 123 0.013 162 0.001 201 0.005 85 0.011 124 0.006 163 0.008 202 0.008 86 0.016 125 0.033 164 0.012 203 <0.001 ' 87 0.011 126 0.026 165 0.004 204 0.011 ' 88 0.134 127 0.010 166 0.035 205 0.015 ' 89 0.011 130 0.316 167 0.016 206 0.013 90 0.026 131 2.007 168 0.028 207 0.011 91 0.017 132 0.051 169 0.060 208 0.004 92 0.010 133 0.033 170 0.018 209 0.011 93 0.049 134 0.059 171 0.013 210 0.021 94 ' 0= .007 ' 1= 35 0.008 172 0.041 211 0.017 .
95 0.01.0 136 0.004 173 0.080 212 0.010 96 0.007 137 0.006 174 0.002 213 0.015 97 0.009 138 0.218 175 0.071 214 0.031 98 1.269* 139 0.039 176 0.003 215 0.031 99 0.006 140 <0.001 177 0.006 216 -- 0.011 100 0.005 141 0.014 178 0.006 217 0.008 101 0.006 142 0.051 179 0.019 218 0.006 102 ' 0= .011 ' 1= 43 0.004 180 0.016 219 0.004 .
103 >3 144 0.018 181 0.012 220 0.005 104 0.010 145 0.033 182 0.008 221 0.008 105 0.067 146 0.624 183 0.025 222 0.008 106 0.012 147 1.563 184 0.077 223 >3 107 0.012 148 0.112 185 0.01.3 224 0.009 108 0.007 149 0.019 186 0.014 225 0.011 109 0.020 150 0.012 187 0.014 226 0.017 110 ' 0= .002 ' 1= 51 0.002 188 0.041 227 0.008 .
111 0.008 152 0.353 189 0.039 228 0.171 ' 112 0.005 153 0.117 190 0.029 229 0.012 114 > 3 154 0.008 191 0.011 230 0.029 115 0.012 155 0.122 192 0.009 231 0.005 116 0.010 156 0.006 193 0.01.2 232 0.012 117 0.004 157 0.016 194 0.065 233 0.040 118 0.005 158 0.194 195 0.038 234 0.032 119 ' 0= .007 ' 196 0.002 235 0.022 .
197 0.066 236 0.024 ' Example 3 Determination of phosphorylated BTK in Ramos cells 1. Reagents and materials Ramos cells: Ramos cells were purchased from American Standard Biological Collection Center ATCC Cell Bank, PR.MI 1640 medium containing L-glutamine, 1.5 gli., of sodium bicarbonate, 2.383 g/L of HEPES solution, 0.11 g/L of sodium pyruvate and 4.5 g/L of glucose was used, added 10% fetal bovine serum FBS, and placed in a 5% CO2, 37 C cell incubator for normal culture;
PRMI 1640 medium: GIBCO, Cat# A10491-01;
Fetal bovine serum (FBS): GIBCO, Cat# 100100-147;
Hank's balanced salt solution (HBSS): GIBCO, Cat# 14025-092;
Immunoglobulin M (IgM): Jackson Immuno, Cat# 109-006-129;
3% hydrogen peroxide (3% H202): Sigma, Cat# 88597-100ML-F;

Phosphorylated BTK HTRF detection kit (BTK phospho-Y223 HTRF kit): Cisbio, Cat#
63ADK017PEH;
Microwell plate reader: Envision, Perkin Elmer;
384-well plate CulturPlateTM384: Perkin Elmer, Cat# 6007680 96-well plate: Corning, Cat# 3799.
2. Methods Ramos cells were starved in PRM I 1640 medium with 1% FBS for 2 hours. The starved Ramos cells were diluted with Hank's balanced salt solution to 5.0 x 106 cells/ml, seeded in a 96-well plate with 20 AL/well (1.0 x 105 cells/well), and cultured in a 5% CO,, 37 C cell incubator.
After culturing for 1 hour, the test compound was diluted with Hank's balanced salt solution in 4-fold gradient to the corresponding concentrations, and then 5 AL/well of the diluted test compound with different concentrations (the final concentrations of the test compound were 3.0, 0.75, 0.188, 0.047, 0.012, 0.0029, 0.0007 and 0.00018 AM, and the final concentration of DMSO
was 0.3%, double replicate wells) or 5 AL/well of control solution (1.5% DMSO, 8 replicate wells) were added to 20 AL/well of cell culture system, which incubated together for another hour, then 5 AL/well of a mixed solution of human immunoglobulin M (final concentration was 10 pg/mL) and hydrogen peroxide (final concentration was 3.3 mM) diluted with Hank's balanced salt solution was added to the treating wells for the test compound and the control treating wells for anti-human immunoglobulin M, and 5 AL/well of Hank's balanced salt solution was added to negative control treating wells. The plate was incubated in a 5%
CO2, 37 C cell incubator for 10 minutes.
10 AL/well of cell lysis buffer was added to each well of a 96-well plate, which was mixed well and lysed at room temperature for 30 minutes. 16 AL/well of lysis buffer was pipetted to a new 384 well plate, and then added 4 AL/well of phosphorylated BTK antibody, centrifuged (1000 rpm) for I minute, then shaken for 1 minute, further centrifuged (1000 rpm) for 1 minute, and finally placed in a constant temperature incubator overnight. Detection was performed on the next day.
3. Detection The 384 well plate incubated overnight in the constant temperature incubator was taken out to detect the luminescence signal using the Envision microwell plate reader at the emission wavelength of 320nm and excitation wavelength of 665nm/615nm. The reading value at 665nm/615nm of each well multiplied by 104 was used as the signal value of each well.
4. Calculation The average signal value of the wells supplemented with the mixed solution of human immunoglobulin M (final concentration was 10 t.ig/mL) and hydrogen peroxide (final concentration was 3.3 mM) without the test compound was regarded as the high value, and the average signal value of the wells without immunoglobulin M stimulation and without the test compound was regarded as the low value. According to the signal value in each well, the inhibition ratio (%) of each concentration of compounds was calculated, and the 205 model in XL-Fit 5.3 software (ID Business Solutions Limited) was used to obtain an IC50 value.
The inhibition ratio is calculated as follows:
inhibition ratio (%) = 100% - {(treating well for the test compound - negative control treating well)/(control treating well for anti-human immunoglobulin M - negative control treating well)}
x 100%, wherein, Treating well for the test compound: represents the signal value of Ramos cells treated with anti-human i.mmunoglobul.in M, hydrogen peroxide and the test compound.
Control treating well for anti-human immunoglobulin M: represents the signal value of Ramos cells treated with anti-human immunoglobulin M, hydrogen peroxide but without the test compound.
Negative control treating well: represents the signal value of Ramos cells without the test compound and without immunoglobulin stimulation.
5. Test results Compound IC50 Compound IC50 Compound I 11050 Compound I IC50 No. (r1111) No. (PM) No. (1114) No, i (04) i 1 0.005 21 0.015 42 0.341 ' 61 0.002 2 0.010 22 0.018 43 0.002 ' 62 0.003 3 0.339 23 0.030 n 44 0.018 i 63 0.005 4 0.480 n 2= 4 0.014 45 0.005 I 64 0.010 . _ _, n 0= .002 25 0.024 46 ' 0.005 os 0.002 _ 6 - 0.002 -26 0.007 -47 0.003 66 0.002 =
7 0.003 27 0.001 48 0.006 67 0.060 , .
8 ' 0.002 n 2= 8 0.002 49 0.001 68 0.002 n 9 . 0.004 = ' 2= 9 0.030 50 0.002 69 0.002 0.010 30 0.008 n 51 0.008 70 0.002 11 ' 0= .155 31 0.006 52 0.018 71 0.006 13 '. 0.001 32 ' 0.030 53 0.025 72 0.097 -14 0.014 33 0.026 54 0.016 73 0.116 0.012 34 0.010 55 0.008 74 0.011 16 0.002 35 0.006 56 0.024 75 0.007 n 17 0.004 36 0.012 57 0.003 76 0.060 18 0.004 37 0.011 58 0.004 77 0.132 19 0.004 40 > 3 59 0.001 78 0.003 0.017 41 0.002 60 0.003 79 n 0.002 80 0.002 12 0.013 38 - 39 0.003 81 n 0= .002 120 0.005 159 0.026 198 0.012 82 0.002 121 0.021 160 0.011 199 0.025 83 0.013 122 0.007 161 0.007 200 0.021 .
84 0.011 123 0.009 162 0.006 201 0.008 85 0.002 124 0.007 163 0.034 202 0.017 86 0.006 125 0.021 164 0.023 203 0.007 87 0.003 126 0.020 165 0.031 204 0.007 88 - 127 0.018 166 0.121 205 0.015 89 0.008 128 - 167 0.012 206 0.007 90 0.007 129 - 168 0.020 207 0.008 91 0.004 130 - 169 0.030 208 0.004 92 0.007 131. - 170 0.01.6 209 0.005 93 0.046 132 0.028 171 0.011 210 0.019 94 0.002 133 0.013 172 0.011 211 0.020 95 0.003 134 0.054 173 0.028 ' 2= 12 0.011 .
96 0.005 135 0.005 174 0.044 213 0.015 97 0.003 136 0.005 175 0.040 214 0.024 98 - 137 0.004 176 ' 0= .016 215 ' 0= .051 99 0.004 138 - 177 ' 0= .021 216 ' 0= .007 100 0.002 139 0.011 178 0.012 217 0.010 101 0.002 140 0.011 179 0.070 218 0.012 102 0.002 141 0.013 180 0.084 219 0.011 103 - 142 0.060 181 0.038 ' 2= 20 0.016 .
104 0.006 143 0.005 182 0.034 221 0.012 105 0.011 144 0.038 183 0.067 222 0.008 106 0.001 145 0.016 184 0.080 223 -. .
107 0.002 146 - 185 0.013 224 0.007 108 0.001 147 - 186 0.010 225 0.009 109 0.004 148 - 187 0.028 226 0.011 110 0.002 149 0.008 188 0.039 227 0.005 111 0.002 150 0.012 189 0.051 ' 2= 28 0.139 .
112 0.003 151 0.028 190 0.040 229 0.010 113 - 152 - 191 0.010 230 0.020 114 - 153 - 192 0.016 231 0.004 115 0.010 154 0.013 193 ' 0= .006 232 ' 0= .008 116 0.011 155 - 194 - 233 0.008 117 0.007 156 0.012 195 - 234 0.010 118 0.001 157 0.025 196 0.007 235 0.013 119 0.002 158 - 197 - 236 0.004 Example 4 Determination of B cell activity in whole blood of rats 1. Reagents and materials Peripheral whole blood of female Wistar rats;
phosphate buffer PBS: GIBCO, Cat# C20012500BI;
anti-rat B220PE antibody (PE anti-rat B220): eBioscience, Cat# 12-0460-82;
anti-rat CD86 FITC antibody (Frrc anti-rat CD86): eBioscience, Cat# 11-0860-82;
times lysis buffer (10 x lysis buffer): I3D Biosciences, Cat# 555899;
fixation butler (IC fixation buffer): Invitrogen, Cat# 00-8222-49;
10 96 well U-shaped bottom plate: Nunc, Cat# 163320;
96 well V-shaped bottom plate: Nunc, Cat# 49952;
dimethyl sulfoxide (DMS0): Sigma-Aldrich, Cat# 34869-414 anti-rat immunoglobulin D (Mouse Anti-rat IgD): Bio-rad, Cat# MCA190;
flow cytometer: BD FACS Canto II, BD.
2. Methods In the determination of the compound activity, the collected peripheral whole blood of rat was added to a 96 well plate at 80 pt/well and cultured in a 5% CO2, 37 C cell incubator. After half an hour, the test compound was diluted with PBS in a 3-fold gradient to the corresponding concentrations, and then the diluted test compound with different concentrations was added to the culture system of rat whole blood at 10 1.LL/well (the final concentration of the test compound was 1.0, 0.33, 0.11, 0.037, 0.012, 0.0041, 0.0014, and 0.0005 ttM, the final concentration of DMSO was 0.3%, double replicate wells), or the control solution (0.3% DMSO, 6 replicate wells) was added to the corresponding well at 10 4/well, which were incubated in the cell incubator for one hour. Then 10 pi/well of anti-rat immunoglobulin D diluted in PBS (the final concentration was 10 p,g/mL) was add to the treating wells of the test compound and control wells for anti-rat immunoglobulin D, or 10 ttL/well of PBS was added to the negative control wells, which were mixed well to continue the culture in a 5% CO2, 37 C cell incubator, and incubated for 18 hours.
On the second day, the 96-well plates were taken out and the flow cytometry antibody mixture (the final concentration of anti-rat B220PE antibody was 1 Ilg/mL and the final concentration of anti-rat CD86 FITC antibody was 1 pg/mL) diluted with PBS was added to each well of plate, which were incubated for 30 minutes in the dark, and then 50 pi of blood from each well was pipetted to the freshly prepared 500 pt of lysis buffer to lyse red blood cells. The plates were shaken for 20 minutes, centrifuged to remove the supernatant, then washed, fixed, and detected on a flow cytometer.
3. Detection The B cell activation in the sample was determined by flow dyeing method.
4. Calculation The average value of the proportion of activated B cells in the wells with anti-rat immunoglobulin D but without the test compound was used as the control treating well for anti-rat immunoglobulin D, and the average value of the proportion of activated B
cells in the wells without immunoglobulin D stimulation and without the test compound was used as the negative control treating well. According to the B cell activation ratio in each well, the inhibition ratio (%) of each concentration was calculated, and then the IC50 value was obtained by using the 205 model in XL-Fit 5.3 software (ID Business Solutions Limited).
The inhibition ratio is calculated as follows:
inhibition ratio (%) = 100% - ((treating well for the test compound - negative control treating well)/(control treating well for anti-rat immunoglobulin D - negative control treating well)} x 100%, wherein, Treating well for the test compound: represents the B cell activation ratio in rat whole blood treated with anti-rat immunoglobulin D and the test compound.
Control treating well for anti-rat immunoglobulin D: represents the B cell activation ratio in rat whole blood treated with anti-rat immunoglobulin D but without the test compound.
Negative control treating well: represents the B cell activation ratio in rat whole blood without the test compound and without immunoglobulin stimulation.
Through the above-mentioned test, the compound of the present invention has a potency to inhibit B cell activation in rat whole blood.

DEMANDE OU BREVET VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND
PLUS D'UN TOME.

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Claims

1. A compound of formula (I):
or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a lautomer thereof, wherein X1 and X2 are each independently CH or N; or, X1 is N, X2 is CR14, wherein R14 is C1-6 alkyl;
X3 and X4 are each independently C or N;
Y1 and Yi are each independently CR10 or N;
R1 and R2 are each independently chosen from hydrogen, deuterium, halogen, C1..6 alkyl, C/-6 alkynyl, C1-6 haloalkyl, C3-6 cycloalkyl and phenyl; or R1 and R2 together with the carbon atoms to which they are attached form the following structures:
wherein R6 is independently chosen from deuteriurn, halogen, hydroxyl, Ci_6 alkyl, C2-6 alkynyl, C1_6 deuteroalkyl and C1.6 haloalkyl; or two R6 together with the carbon atoms to which they are attached form 3-6 membered cycloalkyl; m is 0, 1, 2, 3 or 4; p is 1, 2, 3 or 4;
Z is N or CR7; R7 is chosen from hydrogen, deuterium, C1_6 alkyl, halogen and C1.6 haloalkyl;
or R1 and R2 together with the carbon atoms to which they are attached form provided that R3 is halogen, or both X1 and Xi are not CH at the same time;
R3 is hydrogen, deuterium, halogen or C1-6 haloalkyl;
R4 is hydrogen, halogen, -CN, C1..6 alkyl, C2_6 alkynyl, alkyl)-0H, alkyl)-0-(C1.3 alkyl), -0-(C1..3 alkyl), -CHO, -C(0)NH2, -C(0)NHCH3, -C(0)N(CH3)2 or 3-hydroxyl-oxetan-3-yl, wherein the C1-6 alkyl or C1-3 alkyl is each optionally substituted with one or more deuterium or halo;
Cy is =,wherein R11 is chosen from hydrogen, C1.6 alkyl and C3-6 cycloalkyl, wherein the C1..6 alkyl is optionally substituted with one or more deuterium or halo;
U, V and W are each independently N or CR12; R12 is hydrogen, deuterium or halogen;

R5 is hydrogen, C1_6 alkyl, -C(0)-(C1_6 alkyl), -C(0)-(C3_6 cycloalkyl), -C(0)-phenyl, -C(0)NH-(Ci_6 alkyl), -C(0)NH-(C3.6 cycloalkyl), -C(0)N(Ci_6 alkyl)2, phenyl, 5-membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl, wherein the C1-6 alkyl, C3-6 cycloalkyl, phenyl, 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl is each optionally substituted with one or more groups chosen from:
1) halogen;
2) oxo;
3) -CN;
4) Ci_6 alkyl;
5) C2_6 alkenyl;
6) C2_6 alkynyl;
7) C1.6 alkoxy;
8) C1-6 haloalkyl;
9) -(C1..6 alkyl)-0H;
10) -(Ci..6 a1kyl)-0-(Ci_6 alkyl);
11) C3-6 cycloalkyl;
12) 3-12 membered heterocyclyl optionally substituted with one or more groups chosen from: deuterium, halogen, hydroxyl, oxo, -CN, C1.6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C2-6 alkynyl, C1-6 alkoxy, -(C1.6 alkyl)-CN, -(C1.6 alkyl)-0-(C1-6 alkyl), -(C1.6 a1ky1)-0H, 4-6 membered heterocyclyl and deuterated 4-6 membered heterocyclyl, wherein the C1.6 alkyl, C3-6 cyc1oa1ky1 or 4-6 membered heterocyclyl is each optionally substituted with one or more groups chosen from:
deuterium, halogen, -NH2, -OH, -NH(C1..6 alkyl), -N(C1.6 a1kyl)2 and -NH(C3-6 cycloalkyl);
13) 5-6 membered monocyclic heteroaryl optionally substituted with one or more groups chosen from: halogen, -CN, -(C1.6 alkyl)-CN, -(C1.6 a1kyl)-0H, C1.6 alkyl, C3_6 cycloalkyl, C1.6 alkoxy, -(C1..6 alkyl)-0-(C1.6 alkyl), -(Ci..6 a1kyl)-NH2, -(C1-6 alkyl)-NH(C1.6 alkyl), -(C1.6 alkyl)-N(Ci_6 alky1)2, -(C1.6 alkyl)-NH(C3-6 cycloalkyl) and 4-6 membered heterocyclyl;
14) phenyl optionally substituted with one or more groups chosen from:
halogen, -CN, -(C1.6 alkyl)-CN, -(C1.6 alkyl)-0H, C1_6 alkyl, C3.6 cycloalkyl, C1_6 alkoxy, -(C1.6 alkyl)-0-(C1.6 alkyl), -(C1.6 alkyl)-NH2, -(C1.6 alkyl)-NH(C1.6 alkyl), -(C1-6 a1ky1)-N-(Ci_6 a1ky1)2, -(C1.6 alkyl)-NH(C3.6 cycloalkyl) and 4-6 membered heterocyclyl;
15) -NR.'R.", wherein R.' and Ra" are each independently chosen from hydrogen, Ci_6 alkyl, C3-6 cycloalkyl, -(Ci..6 alkyl)-0-(C1.6 alkyl) and 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with one or more substituents of -(C1..6 a1kyl)-0H, the C1..6 alkyl is optionally substituted with one or more -NRe'Re", and Re' and Re" are each independently chosen from hydrogen, Ci_6 alkyl, -(C1.6 alkyl)-OH and 4-6 membered heterocyclyl;
16) -C(0)NRb'Rb", wherein Rb' and Rb" together with the N atoms to which they are attached form 4-6 membered heterocyclyl optionally substituted with one or more groups chosen from: deuterium, halogen, -OH, C1.6 alkyl, -(C1.6 alkyl)-N112, -(C1.6 alkyl)-NH(C1.6 alkyl), -(Ci_6 alkyl)-N(C1.6 alky1)2, -(C1.6 alkyl)-NH(C3-6 cycloalkyl), -NH2, -NH(C1..6 alkyl), -N(C1..6 alky1)2, -NH(C3.6 cycloalkyl) and -(C1.6 alkyl)-OH; and 17) -C(0)Re, wherein Re is chosen from hydrogen, C1_6 alkyl, C2-6 alkenyl, C2-alkynyl, -(C1.6 alkyl)-OH and -(C1.6 alkyl)-0-(C1.6 alkyl);
R10 is hydrogen, deuterium, halogen, CN, C1..6 alkyl or C1-6 haloalkyl;
provided that if R1 and R2 together with the carbon atoms to which they are attached form the following structures:
.
, then the 3-12 membered heterocyclyl, when substituted, is not piperazin-1-y1 substituted with C1.6 alkyl at both 2- and 6- positions.

2. The cornpound of claim 1, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiorner, a diastereomer or a tautomer thereof, wherein R1 and R2 together with the carbon atorns to which they are attached form i.e. the compound is a compound of formula (1A):

3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a lautorner thereof, wherein R1 and R2 together with the carbon atoms to which they are attached form , X3 is N, X4 is C, Yi is CH, Cy is ', and the cornpound is a compound of formula (I1):

wherein X1 and X2 are each independently CH or N; or, Xi is N, X2 is CR14, wherein R14 is chosen from C1.6 alkyl;
Y2 is CH or N;
R3 is hydrogen, deuterium, halogen or C1-6 haloalkyl;
R4 is hydrogen, halogen, -CN, C1_6 alkyl, -(C1_3 alkyl)-0H, -(C1_3 deuteroalkyl)-0H, -(C1.3 alkyl)-0-(Ci_3 alkyl), -0-(C1-3 alkyl), -CHO, -C(0)N=H2, -C(0)NHCH3, -C(0)N(CH3)2 or 3-hydroxyl-oxetan-3-yl, wherein the C1_6 alkyl is optionally substituted with one or more halo;
W is N or CR12, and R12 is hydrogen or halogen;
R5 is hydrogen, C1_6 alkyl, -C(0)-(C1_6 alkyl), -C(0)-(C3_6 cycloalkyl), -C(0)-phenyl, -C(0)NH-(C1.6 alkyl), -C(0)NH-(C3.6 cycloalkyl), -C(0)N(C1.6 alky1)2, phenyl, 5-rnembered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl, wherein the C1-6 alkyl, C3-6 cycloalkyl, phenyl, 5-6 membered rnonocyclic heteroaryl or 8-10 membered bicyclic heteroaryl is each optionally substituted with one or more groups chosen from:
1) halogen;
2) oxo;
3) -CN;
4) Ci_6 alkyl;
5) C2_6 alkenyl;
6) C2_6 alkynyl;
7) C1-6 alkoxy;
8) C1-6 haloalkyl;
9) -(Ci_6 alkyl)-OH;
10) -(C1_6 alkyl)-0-(C1-6 alkyl);
1 1) C3-6 cycloalkyl;
12) 3-12 membered heterocyclyl optionally substituted with one or rnore substituents chosen frorn halogen, hydroxyl, oxo, -CN, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C2_6 alkynyl, C1-6 alkoxy, -(C1_6 alkyl)-CN, -(C1_6 alkyl)-0-(C1-6 alkyl), -(C1_6 a1kyl)-0H, 4-6 membered heterocyclyl, 4-6 membered fluoroheterocyclyl and deuterated 4-6 mernbered heterocyclyl, wherein the C1-6 alkyl is optionally substituted with one or more -OH;
13) 5-6 membered monocyclic heteroaryl optionally substituted with one or more substituents chosen from halogen, -CN, -(C1.6 alkyl)-CN, -(C1.6 alkyl)-0H, C1-alkyl, C3-6 cycloalkyl, C1-6 alkoxy, -(C1-6 alkyl)-0-(C1-6 alkyl), -(C1-6 a1kyl)-N112, -(Ci_6 a1kyl)-NH(Ci_6 alkyl), -(C1_6 a1kyl)-N(Ci_6 alky1)2, -(Ci_6 alkyl)-NH(C3-6 cycloalkyl) and 4-6 membered heterocyclyl;

14) phenyl optionally substituted with one or more substituents chosen from halogen, -CN, -(C1.6 alkyl)-CN, -(C1.6 alkyl)-OH, C1-6 alkyl, C3-6 cycloalkyl, C1_6 alkoxy, -(C1_6 alkyl)-0(C1_6 alkyl), -(C1_6 alkyl)-NH2, -(Ci_6 alkyl)-NH(C1_6 alkyl), -(C1-6 alkyl)-N(C1_6 alky1)2, -(C1_6 alkyl)-NH(C3_6 cycloalkyl) and 4-6 membered heterocyclyl;
15) -NRa'Ra", wherein Ra' and Ra" are each independently chosen from hydrogen, C1.6 alkyl, C3-6 cycloalkyl, -(C1_6 alkyl)-0-(Ci.6 alkyl) and 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with one or more substituents of -(C1_6 alkyl)-0H, the C1_6 alkyl is optionally substituted with one or more -NRe'Re", and R,' and Re" are each independently chosen from hydrogen, C1_6 alkyl, -(C1_6 alkyl)-OH and 4-6 membered heterocyclyl;
16) -C(0)NRb'Rb", wherein Rb' and Rb" together with the N atoms to which they are attached form 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with one or more substituents chosen from halogen, -OH, C1_6 alkyl, -(C1_6 a1kyl)-NH2, -(C1.6 alkyl)-NH(C1.6 alkyl), -(C1-6 a1kyl)-N(C1-6 a1kyl)2, -(C1-6 a1kyl)-NH(C3_6 cycloalkyl) and -(Ci_6 a1kyl)-0H;
and 17) -C(0)Rc, wherein R, is chosen from hydrogen, C1_6 alkyl, C/-6 alkenyl, C2-alkynyl and -(Ci_6 alkyl)-0-(Ci_6 alkyl);
R6 is halogen, Ci_6 alkyl or hydroxyl; and m is 0, 1, 2 or 3.

4. The compound of claim 2, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a lautomer thereof, wherein R1 and R2 together with the carbon atoms to which they are attached forrn , X3 is N, X4 is C, Y1 is CH, Cy and the compound is a compound of formula wherein Xi and X2 are each independently CH or N; or, Xi is N, X2 is CR14, wherein R14 is chosen from C1-6 alkyl;
Y2 is CH or N;
R3 is hydrogen, deuterium, halogen or C1_6 haloalkyl;

R4 is hydrogen, halogen, -CN, C1-6 alkyl, -(Ci_3 alkyl)-0H, deuteroalkyl)-0H, -(C1.3 alkyl)-0-(Ci_3 alkyl), -0-(C1-3 alkyl), -CHO, -C(0)N=H2, -C(0)NHCH3, -C(0)N(CH3)2 or 3-hydroxyl-oxetan-3-yl, wherein the Ci_6 alkyl is optionally substituted with one or more halo;
U and V are each independently chosen from N or CH;
R5 is hydrogen, C 1_6 alkyl, -C(0)-(C 1_6 alkyl), -C(0)-(C3_6 cycloalkyl), -C(0)-phenyl, -C(0)NH-(C1.6 alkyl), -(40)NH-(C3.6 cycloalkyl), -C(0)N(C1.6 alkyl)2, phenyl, 5-membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl, wherein the C1-6 alkyl, C3-6 cycloalkyl, phenyl, 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl is each optionally substituted with one or more groups chosen from:
1) halogen;
2) oxo;
3) -CN;
4) Ci_6 alkyl;
5) C2_6 alkenyl;
6) C2_6 alkynyl;
7) C1-6 alkoxy;
8) C1-6 haloalkyl;
9) -(Ci_6 alkyl)-OH;
10) -(C1_6 alkyl)-0-(Ci_6 alkyl);
11) C3-6 cycloalkyl;
12) 3-12 membered heterocyclyl optionally substituted with one or more substituents chosen from halogen, hydroxyl, oxo, -CN, C1_6 alkyl, C1-6 haloallcyl, C3-6 cycloalkyl, C2_6 alkynyl, C1-6 alkoxy, -(C1_6 alkyl)-CN, -(C1_6 alkyl)-0-(C1-6 alkyl), -(C1.6 a1ky1)-0H, 4-6 membered heterocyclyl, 4-6 membered fluoroheterocyclyl and deuterated 4-6 membered heterocyclyl, wherein the C1-6 alkyl is optionally substituted with one or more -OH;
13) 5-6 membered monocyclic heteroaryl optionally substituted with one or more substituents chosen from halogen, -CN, -(Ci_6 alkyl)-CN, -(Ci_6 a1kyl)-0H, C1-alkyl, C3-6 cycloalkyl, Ci..6 alkoxy, -(Ci_6 alkyl)-0-(Ci_6 alkyl), -(C1_6 a1kyl)-N112, -(C1_6 a1kyl)-NH(Ci_6 alkyl), -(Ci_6 alkyl)-N(Ci_6 alky1)2, -(Ci_6 alkyl)-NH(C3-6 cycloalkyl) and 4-6 membered heterocyclyl;
14) phenyl optionally substituted with one or more substituents chosen from halogen, -CN, -(Ci_6 alkyl)-CN, -(Ci_6 alkyl)-0H, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, a1ky1)-0(Cl_6 -(Ci_6 alkyl)-NH2, -(Ci_6 alkyl)-NH(Ci_6 alkyl), -(C1_6 alkyl)-N(Ci_6 alky1)2, -(Ci_6 alkyl)-NH(C3_6 cycloalkyl) and 4-6 membered heterocyclyl;
15) -NIVRa", wherein Ra' and Ra" are each independently chosen from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, -(Ci_6 a1ky1)-0-(Ci_6 alkyl) and 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with one or more substituents of -(Ci_6 alkyl)-0H, the C1-6 alkyl is optionally substituted with one or more -NRe'Re", and R,' and Re" are each independently chosen from hydrogen, C1_6 alkyl, -(C1_6 alkyl)-OH and 4-6 membered heterocyclyl;

16) -C(0)NRb'Rb", wherein Rb' and Rb" together with the N atoms to which they are attached form 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with one or more substituents chosen from halogen, -OH, C1..6 alkyl, -(C1..6 alkyl)-NH2, -(C1.6 alkyl)-NH(C1.6 alkyl), -(C1-6 alkyl)-N(C1.6 alky1)2, -(C1.6 alkyl)-NH(C3.6 cycloalkyl) and -(C1.6 alkyl)-OH;
and 17) -C(0)1te, wherein Ite is chosen from hydrogen, C1-6 alkyl, C2-6 alkenyl, alkynyl and -(C1_6 alkyl)-0-(C1_6 alkyl);
R6 is halogen, C1.6 alkyl or hydroxyl;
m is 0, 1, 2 or 3; and R11 is hydrogen, C1-6 alkyl or C1_6 deuteroalkyl;
provided that the 3-12 membered heterocyclyl, when substituted, is not piperazin-l-yl substituted with C1.6 alkyl at both 2- and 6- positions.

5. The cornpound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein both Xi and X2 are CH, or one of Xi and X,) is N, and the other is CH.

6. The cornpound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein Y2 is CH.

7. The cornpound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein R3 is hydrogen or halogen.

8. The cornpound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein R4 is C1_6 alkyl, -(C1.3 alkyl)-OH, -(C1_3 deuteroalkyl)-OH, -(C1_3 alkyl)-0-(C1.3 alkyl) or -CHO, wherein the Ci_6 alkyl is optionally substituted with one or more halo.

9. The cornpound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein R3 is hydrogen, and R4 is -(C1.3 alkyl)-OH.

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein R5 is chosen from wherein R21 is chosen from C1.6 alkyl, C1_6 haloalkyl and -(C1_6 alkyl)-0-(Ci_6 alkyl);
n is 0, 1 or 2;
R22 and R23 are each independently chosen from hydrogen, -CN, C1.6 alkyl, C1_6 haloalkyl, -(C1_6 alkyl)-0-(Ci_6 alkyl), 4-6 membered heterocyclyl or -C(0)R,, and R, is chosen from hydrogen, Ci_6 alkyl or -(C1_6 alkyl)-0-(Ci_6 alkyl);
R/4 is chosen from hydrogen, C1_6 alkyl, -(C1_6 alkyl)-0-(C1_6 alkyl), or -C(0)NRb'Rb", wherein Rb' and Rb" together with the N atoms to which they are attached form membered heterocyclyl;
A1, A, and A3 are each independently CH or N; and R13 is chosen from:
1) hydrogen;
2) CI.6 alkyl;
3) Ci_6 alkoxy;
4) halogen;
5) C3-6 cycloalkyl;
6) 3-12 membered heterocyclyl optionally substituted with one or more substituents chosen from oxo, -CN, C1.6 alkyl, C1_6 alkoxy, -(C1_6 alkyl)-CN, -(C1-6 alkyl)-(C1_6 alkyl), 4-6 membered heterocyclyl and deuterated 4-6 mernbered heterocyclyl, wherein the Ci_6 alkyl is optionally substituted with one or more -OH;
7) phenyl optionally substituted with one or more substituents chosen from membered heterocyclyl;
8) -NRa'Ra", wherein Ra' and Ra" are each independently chosen frorn hydrogen, C1_6 alkyl, -(Ci_6 alkyl)-0-(Ci_6 alkyl) and 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with -(C1_6 alkyl)-0H, the C1_6 alkyl is optionally substituted with one or more -NR,'Re", and R,' and R,"
are each independently chosen from hydrogen, C1-6 alkyl, -(C1_6 alkyl)-OH and 6 membered heterocyclyl; and 9) -C(0)NRb'Rh", wherein Rb' and Rb" together with the N atoms to which they are attached form 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with one or more C1.6 alkyl;
provided that if R1 and R2 together with the carbon atoms to which they are attached form the following structures:

, then the 3-12 membered heterocyclyl, when substituted, is not piperazin-l-y1 substituted with C1-6 alkyl at both 2- and 6- positions.

11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein R13 is piperazinyl optionally substituted with one or more substituents chosen from C1_6 alkyl and 4-5 membered heterocyclyl;
provided thatif R1 and R2 together with the carbon atoms to which they are attached form the following structures:
=, then the 3-12 membered heterocyclyl, when substituted, is not piperazin-l-yl substituted with C1-6 alkyl at both 2- and 6- positions.

12. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein R5 is chosen from wherein R24, R24', R25, R259, R27 and R279 are each independently chosen from hydrogen, oxo and C1-6 alkyl;
R26 iS C1-6 alkyl, -(C1.6 alkyl)-0-(C1_6 alkyl) or tetrahydrofuranyl;
R28 iS alkoxy; R29 is hydrogen or -(C1..6 a1kyl)-0H;
R30 is C1-6 alkyl; and A1, A2 and A3 are each independently CH or N.

13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein R5 , wherein& A2 and A3 are each independently CH or N, and R'm and R24' are eacn maependently chosen from hydrogen, oxo and C1-6 alkyl.

14. The compound of claim 13, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein R24 and R24' are each independently chosen from hydrogen and C1-6 alkyl.

15. The compound of any one of claims 13-14, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein Al, A2 and A3 are all CH, or A1 is N, and both A2 and A3 are CH, or A3 is N, and both A1 and A2 are CH.

16. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein R5 is chosen from:
<DIG>
wherein Ril is C1_6 alkyl; R22 is chosen from hydrogen, Ci_6 alkyl and 4 membered heterocyclyl; A1 and A, are respectively CH; and R24 and R24' are each independently chosen from hydrogen and C1-6 alkyl.

17. The compound of any one of claims 4-16, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein = *, wherein R11 is C1-6 alkyl or C1-6 deuteroalkyl.

18. The compound of claim 4, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiorner, a diastereomer or a tautomer thereof, wherein both X1 and X2 are CH, or one of Xi and X2 is N, and the other is CH; Y) is CH; R3 is hydrogen; R4 is -(C1.3 alkyl)-0H; U is CH, V is N or CH, and R11 is CI_3 alkyl; R5 is chosen from , whereinR24 and R24' are each independently chosen from hydrogen, oxo and C1_6 alkyl, both A1 and A, are CH, or A1 is N and A2 is CH; R6 is C1_6 alkyl;
and m is 0 or 2.

19. The compound of any one of claims 4-18, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein both U and V are CH, and R11 is methyl.

20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein R6 iS C1_3 alkyl; and m is 2.

21. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein R6 together with the five-membered ring to which they are attached forms

22. The compound of claim 4, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein both X1 and X, are CH; Y2 is CH; R3 is hydrogen; R4 iS -(C1_3 alkyl)-0H; both U and V are CH, and R11 is methyl; R5 is chosen from , wherein R24 is C1-3 alkyl, and both A1 and A2 are CH; and R6 together with the five-membered ring to which they are attached forms

23. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiorner, a diastereomer or a tautomer thereof, wherein the compound is a compound of formula (IB)

24. The compound of claim 23, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein the compound is a compound of formula (IV):
wherein X1 and X2 are each independently CH or N; or, X1 is N, X, is CR14, wherein R14 is chosen from CI.6 alkyl;
Y2 is CH or N;
R3 is hydrogen, deuterium, halogen or C1-6 haloalkyl;
R4 is hydrogen, halogen, -CN, C1-6 alkyl, -(C1.3 alkyl)-0H, -(C1.3 deuteroalkyl)-0H, alkyl)-0-(Ci..3 alkyl), -0-(C1..3 alkyl), -CHO, -C(0)NH2, -C(0)NHCH3, -C(0)N(CH3)2 or 3-hydroxyl-oxetan-3-yl, wherein the C1_6 alkyl is optionally substituted with one or more halo;
U and V are each independently chosen from N or CH;
Z is N or CH;
R5 is hydrogen, C1_6 alkyl, -C(0)-(Ci_6 alkyl), -C(0)-(C3_6 cycloalkyl), -C(0)-phenyl, -C(0)NH-(C1.6 alkyl), -C(0)NH-(C3.6 cycloalkyl), -C(0)N(C1.6 alkyl)2, phenyl, 5-membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl, wherein the C1_6 alkyl, C3-6 cycloalkyl, phenyl, 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl is each optionally substituted with one or more groups chosen from:
1) halogen;
2) oxo;
3) -CN;
4) Ci_6 alkyl;
5) C2-6 alkenyl;
6) C2_6 alkynyl;
7) C1-6 alkoxy;
8) C1..6 haloalkyl;

9) -(C1-6 alkyl)-OH;
10) -(C1-6 alkyl)-O-(C1-6 alkyl);
11) C3-6 cycloalkyl;
12) 3-12 membered heterocyclyl optionally substituted with one or more substituents chosen from halogen, hydroxyl, oxo, -CN, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C2-6 alkynyl, C1-6 alkoxy, -(C1-6 alkyl)-CN, -(C1-6 alkyl)-O-(C1-6 alkyl), -(C1-6 alkyl)-OH, 4-6 membered heterocyclyl, 4-6 membered fluoroheterocyclyl and deuterated 4-6 membered heterocyclyl, wherein the C1-6 alkyl is optionally substituted with one or more -OH;
13) 5-6 membered monocyclic heteroaryl optionally substituted with one or more substituents chosen from halogen, -CN, -(C1-6 alkyl)-CN, -(C1-6 alkyl)-OH, C1-alkyl, C3-6 cycloalkyl, C1-6 alkoxy, -(C1-6 alkyl)-O-(C1-6 alkyl), -(C1-6 alkyl)-NH2, -(C1-6 alkyl)-NH(C1-6 alkyl), -(C1-6 alkyl)-N(C1-6 alkyl)2, -(C1-6 alkyl)-NH(C3-6 cycloalkyl) and 4-6 membered heterocyclyl;
14) phenyl optionally substituted with one or more substituents chosen from halogen, -CN, -(C1-6 alkyl)-CN, -(C1-6 alkyl)-OH, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, -(C1-6 alkyl)-O(C1-6 alkyl), -(C1-6 alkyl)-NH2, -(C1-6 alkyl)-NH(C1-6 alkyl), -(C1-6 alkyl)-N(C1-6 alkyl)2, -(C1-6 alkyl)-NH(C3-6 cycloalkyl) and 4-6 membered heterocyclyl;
15) -NR a'R a", wherein R a' and R a" are each independently chosen from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, -(C1-6 alkyl)-O-(C1-6 alkyl) and 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with one or more substituents of -(C1-6 alkyl)-OH, the C1-6 alkyl is optionally substituted with one or more -NR e'R e", and R e' and R e" are each independently chosen from hydrogen, C1-6 alkyl, -(C1-6 alkyl)-OH and 4-6 membered heterocyclyl;
16) -C(O)NR b'R b", wherein R b' and R b" together with the N atoms to which they are attached form 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with one or more substituents chosen from halogen, -OH, C1-6 alkyl, -(C1-6 akyl)-NH2, -(C1-6 alkyl)-NH(C1-6 alkyl), -(C1-alkyl)-N(C1-6 alkyl)2, -(C1-6 alkyl)-NH(C3-6 cycloalkyl) and -(C1-6 alkyl)-OH;
and 17) -C(O)R c, wherein R c is chosen from hydrogen, C1-6 alkyl, C2-6 alkenyl, alkynyl and -(C1-6 alkyl)-O-(C1-6 alkyl);
R6 is halogen, C1-6 alkyl or hydroxyl;
m is 0, 1, 2 or 3; and R11 is hydrogen, C1-6 alkyl or C1-6 deuteroalkyl.

25. The compound of any one of claims 23-24, or a pharmaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein Y2 is CH.

26. The compound of any one of claims 23-25, or a pharrnaceutically acceptable salt thereof, or a solvate, a racemic mixture, an enantiomer, a diastereomer or a tautomer thereof, wherein R5 is chosen from:
wherein R21 is chosen from C1_6 alkyl, C1_6 haloalkyl and -(C1_6 alkyl)-0-(C1-6 alkyl);
n is 0, 1 or 2;
R22 and R23 are each independently chosen from hydrogen, -CN, C1.6 alkyl, C1.6 haloalkyl, -(C1_6 alkyl)-0-(C1_6 alkyl), 4-6 membered heterocyclyl or -C(0)Re, and R, is chosen from hydrogen, C1_6 alkyl or -(C1_6 alkyl)-0-(C1_6 alkyl);
R24 is chosen from hydrogen, C1_6 alkyl, -(C1_6 alkyl)-0-(C1_6 alkyl), or -C(0)NRb'Rb", wherein Rb' and Rb" together with the N atoms to which they are attached form membered heterocyclyl;
A1, A2 and A3 are each independently CH or N; and R13 is chosen from:
1) hydrogen;
2) Ci_6 alkyl;
3) C1_6 alkoxy;
4) halogen;
5) C3-6 cycloalkyl;
6) 4-8 membered heterocyclyl optionally substituted with one or more substituents chosen from oxo, -CN, C1_6 alkyl, C1_6 alkoxy, -(C1_6 alkyl)-CN, -(C1-6 alky1)-0-(C1-6 alkyl), 4-6 membered heterocyclyl and deuterated 4-6 membered heterocyclyl, wherein the C1_6 alkyl is optionally substituted with one or more -OH;
7) phenyl optionally substituted with one or more substituents chosen from 4-6 membered heterocyclyl;
8) -NRõ'Ra", wherein R,' and R," are each independently chosen from hydrogen, alkyl, -(C1_6 alkyl)-0-(C1_6 alkyl) and 4-6 membered heterocyclyl, wherein the membered heterocyclyl is optionally substituted with one or more -(C1_6 alkyl)-0H, the C1_6 alkyl is optionally substituted with one or more -NRe'lle", and Re' and R,"
are each independently chosen from hydrogen, C1_6 alkyl, -(C1_6 alkyl)-OH and membered heterocyclyl; and 9) -C(0)NRt,'Rb", wherein Rb' and Rt," together with the N atorns to which they are attached form 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted with one or more C1-6 alkyl.

27. The cornpound of any one of claims 23-26, or a pharrnaceutically acceptable salt thereof, or a solvate, a racernic mixture, an enantiomer, a diastereorner or a tautomer thereof, wherein both X1 and X2 are CH, or one of X1 and X2 is N, and the other is CH;
Y2 is CH;
R3 is hydrogen;
R4 is -(C1.3 alkyl)-OH;
Z is CH;
U is CH, and V is N or CH;
R5 is , wherein A1 and A2 are each independently CH or N, and R13 is 4-6 membered heterocyclyl optionally substituted with one or more substituents chosen frorn oxo, C1.6 alkyl, C1.6 alkoxy, alkyl)-0-(C1.6 alkyl) and 4-6 membered heterocyclyl; R/2 is chosen frorn hydrogen, -CN, C1.6 alkyl, C1.6 haloalkyl, -(C1.6 alkyl)-0-(C1.6 alkyl), 4-6 membered heterocyclyl or -C(0)Rc, and Re is chosen from hydrogen, C1-6 alkyl or -(C1_6 alkyl)-0-(C1.6 alkyl);
R6 is hydrogen or halogen;
m is 0, 1 or 2; and R11 is C1.3 alkyl.

28. The compound of clairn 1, or a pharmaceutically acceptable salt thereof, or a solvate, a racernic mixture, an enantiorner, a diastereorner or a tautorner thereof, which is chosen from:

29. A pharmaceutical composition, comprising the compound of any one of claims 1-28 andlor a pharmaceutically acceptable salt thereof, and optionally cornprising a pharmaceutically acceptable excipient.

30. A method of in vivo or in vitro inhibiting the activity of BTK, comprising contacting BTK
with an effective amount of the compound of any one of claims 1-28, and/or a pharrnaceutically acceptable salt thereof.

31. Use of the compound of any one of claims 1-28 and/or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a disease mediated by BTK or at least in part by BTK, preferably for treating or preventing cancer, an inflammatory disease or autoimmune disease, wherein the cancer is preferably solid tumor or hematologic malignancy, including lymphoma, leukemia and myeloma; the cancer is more preferably chosen from B cell malignancy, diffuse large B-cell lymphoma (DLBCL), large B-cell lymphoma (LBCL), B-cell lymphoma, mantle cell lymphorna, follicular lymphoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, Waldenstrom rnacroglobulinemia, marginal zone lymphoma, Burkitt's lymphoma, non-Burkitt's hi ghl y degree B cell malignant lymphoma, extranodal marginal-zone B-cell lymphoma, small lymphotic lyrnphoma (SLL), lymphoblastic lymphoma, lymphocytic leukemia, rnyelogenous leukemia, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), human acute rnonocytic leukemia, acute lymphocytic leukemia (ALL), B
cell acute lymphocytic leukemia (B-ALL), hairy cell leukemia, chronic lymphocytic leukemia (CLL) (such as high risk CLL), myelodysplastic syndrome, acute lymphoblastic leukemia, myeloma (such as rnultiple myeloma) or graft versus host disease;
and the inflammatory disease or autoimmune disease is preferably chosen from: systemic inflammation and local inflammation, arthritis, rheumatoid arthritis, inflammation associated with immunosuppression, organ-graft refection, allergic disease, ulcerative colitis, Crohn's disease, dermatitis, asthma, lupus erythematosus, Sjogren syndrome, multiple sclerosis, scleroderma, multiple sclerosis osteoporosis, idiopathic thrombocytopenic purpura, autoirnmune hemolytic anemia, antineutrophil cytoplasmatic antibody vasculitis, chronic obstructive pulmonary disease, psoriasis, sicca syndrome, pemphigus valgaris, and diseases associated with kidney transplantation.

32. A method of treating or preventing a disease in a subject, comprising administering to the subject in need thereof an effective amount of the compound of any one of claims 1-28, and/or a pharmaceutically acceptable salt thereof, wherein the disease is a disease mediated by BTK or al least in part by BTK; the disease is preferably cancer, an inflammatory disease or autoimmune disease; the cancer is preferably solid turnor or hematologic malignancy, including lymphoma, leukemia and myeloma; the cancer is more preferably chosen from B
cell malignancy, diffuse large B-cell lymphoma (DLBCL), large B-cell lymphoma (LBCL), B-cell lyrnphoma, mantle cell lymphoma, follicular lymphoma, non-Hodgkin's lymphoma, Hodgkin's lymphorna, Waldenstrom macroglobulinemia, marginal zone lymphoma, Burkitt's lymphoma, non-Burkitt's highly degree B cell malignant lymphoma, extranodal marginal-zone B-cell lymphoma, small lymphotic lymphoma (S1.1), lymphoblastic lymphoma, lymphocytic leukemia, myelogenous leukemia, acute myelogenous leukemia (AML), chronic rnyelogenous leukemia (CML), human acute monocytic leukemia, acute lyrnphocytic leukemia (ALL), B cell acute lyrnphocytic leukemia (B-ALL), hairy cell leukemia, chronic lyrnphocytic leukemia (CLL) (such as high risk CLL), myelodysplastic syndrome, acute lymphoblastic leukemia, myeloma (such as multiple myeloma) or graft versus host disease; and the inflammatory disease or autoimmune disease is preferably chosen from: systemic inflammation and local inflarnmation, arthritis, rheumatoid arthritis, inflammation associated with immunosuppression, organ-graft refection, allergic disease, ulcerative colitis, Crohn's disease, dermatitis, asthma, lupus erythematosus, Sjogren syndrome, multiple sclerosis, scleroderrna, multiple sclerosis osteoporosis, idiopathic thrombocytopenic purpura, autoirmnune hemolytic anemia, antineutrophil cytoplasmatic antibody vasculitis, chronic obstructive pulmonary disease, psoriasis, sicca syndrome, pemphigus valgaris, and diseases associated with kidney transplantation.

33. The compound of any one of claims 1-28 and/or a pharmaceutically acceptable salt thereof, for use as a medicament.

34. The cornpound of any one of claims 1-28 and/or a pharmaceutically acceptable salt thereof, for use in treating or preventing a disease mediated by BTK or at least in part by BTK, and preferably for use in treating or preventing cancer, an inflammatory disease or autoimmune disease, wherein the cancer is preferably solid tumor or hematologic malignancy, including lymphoma, leukemia and myeloma; the cancer is more preferably chosen from B
cell malignancy, diffuse large B-cell lymphoma (DLBCL), large B-cell lymphoma (LBCL), B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, Waldenstrom macroglobulinemia, marginal zone lymphoma, Burkitt's lymphoma, non-Burkitt's highly degree B cell malignant lymphoma, extranodal marginal-zone B-cell lymphoma, small lymphotic lymphoma (SLL), lymphoblastic lymphoma, lymphocytic leukemia, myelogenous leukemia, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), human acute monocytic leukemia, acute lymphocytic leukemia (ALL), B cell acute lymphocytic leukemia (B-ALL), hairy cell leukemia, chronic lymphocytic leukemia (CLL) (such as high risk CLL), myelodysplastic syndrome, acute lyrnphoblastic leukemia, rnyeloma (such as multiple rnyeloma) or graft versus host disease; and the inflammatory disease or autoimmune disease is preferably chosen from: systemic inflammation and local inflamrnation, arthritis, rheumatoid arthritis, inflammation associated with immunosuppression, organ-graft refection, allergic disease, ulcerative colitis, Crohn's disease, dermatitis, asthma, lupus erythematosus, Sjogren syndrome, multiple sclerosis, scleroderma, multiple sclerosis osteoporosis, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, antineutrophil cytoplasmatic antibody vasculitis, chronic obstructive pulmonary disease, psoriasis, sicca syndrome, pemphigus valgaris, and diseases associated with kidney transplantation.

35. A pharmaceutical combination, comprising the compound of any one of claims 1-28 and/or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent, wherein the therapeutic agent is preferably chosen from: an anti-inflammatory agent, an immunomodulator or an anti-tumor active agent, wherein the anti-tumor active agent includes a chemotherapeutic agent, an irnmune checkpoint inhibitor or agonist, and a targeted therapeutic agent.

36. A compound of formula ( VI):
or a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautorner thereof, wherein Xi, X2, X3, X4, RI, R2 and R3 are as defined in any one of claims 1-28;
R31, is -CHO, -C1..3 alkyl-OH, -C1_3 alkyl-OAc, C1_3 alkyl, -C(0)-Ci..3 alkyl or C1_3 haloalkyl, and R32 is halogen, -B(OH)2, -B(0C1_6 and R is hydrogen or C1-6 alkyl.

37. The compound of claim 36, which is wherein Z is N or CR7; R7 and R8 are each independently hydrogen or halogen; R9 is halogen or C1_6 alkyl;
and n is 1 or 2.

38. The compound of claim 36, which is chosen from: